2,2-Di-substituted 1alpha,25-dihydroxy-19-norvitamin D derivative

ABSTRACT

A novel 2,2-di-substituted 19-norvitamin D derivative. It is a compound represented by the general formula (I) wherein R1 and R2 are the same or different and each represents hydroxy and A represents hydrogen, or an unsubstituted linear or branched alkyl.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the U.S. national stage application of InternationalApplication PCT/JP2003/013053, filed Oct. 10, 2003, which internationalapplication was published on Apr. 22, 2004, as International PublicationWO2004/033420 in the Japanese language. The International Applicationclaims priority of Japanese Patent Applications No. 2002-297366 filedOct. 10, 2002 and No. 2003-024183 filed Jan. 31, 2003.

TECHNICAL FIELD

The present invention relates to novel vitamin D derivatives, and moreparticularly to novel 2,2-disubstituted-19-norvitamin D derivatives andnovel 20-epi-19-norvitamin D derivatives.

BACKGROUND ART

Activated form of vitamin D₃ (1α,25-dihydroxyvitamin D₃, 1,25-(OH)₂D₃)is known as a metabolic regulatory hormone of calcium and phosphorus,and it exhibits various biological activities such as cellular induceddifferentiation, suppression of proliferation, and immunomodulation.These activities are expressed by transcription control of target genemediated by the vitamin D receptor (VDR) that exists in the nucleus.1,25-(OH)₂D₃ is applied to treatment of renal osteodystrophy,D-resistant rickets, hypoparathyroidism, osteoporosis, and psoriasis. Itis also expected as a candidate of therapeutic agent against cancers andimmune diseases. However, administration of effective amounts astherapeutic agent against cancers and immune diseases causes harmfulhypercalcemia. Thus, it has been desired to develop vitamin Dderivatives that dissociate an increasing activity of serum calcium froma cellular induced differentiation activity. In the study of synthesisof the derivatives have selectivity of cellular induced differentiationactivity, attention has been focused mostly on modification of the sidechain of the derivatives. However, DeLuca et al. have been prepared theA-ring modified by removing the 19-exomethylene group from 1,25-(OH)₂D₃,that is, 19-nor-1α,25-dihydroxyvitamin D₃ (hereinafter referred to as19-nor-1,25-(OH)₂D₃)(Perlman K. L., Swenson R. E., Paaren H. E., SchnoesH. K., DeLuca H. F., Tetrahedron Lett., 1991, 32, 7663-7666.). Comparingthe biological activities of 19-nor-1,25-(OH)2D₃ with one of theactivated 1,25-(OH)2D₃, it was shown that VDR affinity was reduced toapproximately one-third and the bone resorption activity was reduced toone-tenth or less of 1,25-(OH)₂D₃, but 19-nor-1,25-(OH)₂D₃ stillretained the cellular effects equivalent to 1,25-(OH)₂D₃.19-nor-1,25-(OH)₂D₃ revealed a selective activity profile with potentcellular differentiation and very low calcium mobilizing activity. Inaddition, 19-norvitamin D derivatives with a variety of substituents atC-2 position on the A-ring have been synthesized and literature dataconcerning interesting biological potency of 2-substituted 19-norvitaminD derivatives have been accumulated (Sicinski R. R., Perlman K. L.,DeLuca H. F., J. Med. Chem., 1994, 37, 3730-3738; Sicinski R. R., PrahlJ. M., Smith C. M., DeLuca H. F., J. Med. Chem., 1998, 41, 4662-4674;Sicinski R. R., Rotkiewicz P., Kolinski A., Sicinska W., Prahl J. M.,Smith C. M., DeLuca H. F., J. Med. Chem., 2002, 45, 3366-3380; YukikoIwasaki et al., The 121^(st) Annual Meeting of the PharmaceuticalSociety of Japan, Abstract 3, p 17, 29[PB]II-011, 2001 (Sapporo);Akihiro Yoshida et al, The 121^(st) Annual Meeting of the PharmaceuticalSociety of Japan, Abstract 3, p 17, 29[PB]II-014, 2001 (Sapporo); YukikoIwasaki et al., The 122^(nd) Annual Meeting of the PharmaceuticalSociety of Japan, Abstract 3, p 180, 28[P]I-184, 2002 (Chiba); MasatoShimizu et al, The 56^(th) Annual Meeting of the Vitamin Society ofJapan, Abstract, Vitamin, 76, 155-156, 2002 (Tokyo); Masato Shimizu etal, 28^(th) Symposium on Progress in Organic Reactions andSyntheses—Applications in the Life Sciences-, Abstract, pp 234-235, 2002(Tokyo)). Introduction of an alkyl or alkylidene moiety at C-2 positionof 19-nor-1,25-(OH)₂D₃ causes increased activity of serum calcium aswell as cellular induced differentiation (Sicinski R. R., Prahl J. M.,Smith C. M., DeLuca H. F., J. Med. Chem., 1998, 41, 4662-4674; SicinskiR. R., Rotkiewicz P., Kolinski A., Sicinska W., Prahl J. M., Smith C.M., DeLuca H. F., J. Med. Chem., 2002, 45, 3366-3380.).

However, in the conventional synthetic studies of 2-substituted19-norvitamin D derivatives, most of the derivatives have a singlesubstituent at C-2 position. Concerning 20-epi-19-norvitamin Dderivatives, 19-norvitamin D derivatives bearing 2-methyl, 2-ethyl or2-hydroxymethyl moiety have been synthesized so far. (Sicinski R. R.,Prahl J. M., Smith C. M., DeLuca H. F., J. Med. Chem., 1998, 41,4662-4674; Sicinski R. R., Rotkiewicz P., Kolinski A., Sicinska W, PrahlJ. M., Smith C. M., DeLuca H. F., J. Med. Chem., 2002, 45, 3366-3380.).It has been desired to develop derivatives having more excellentbiological activities.

DISCLOSURE OF THE INVENTION

An object of the present invention is to synthesize and provide a novel2,2-disubsututed-19-norvitamin D derivative and a novel20-epi-19-norvitamin D derivative. A further object of the presentinvention is to evaluate biological activities of the synthesized novel2,2-disubsututed-19-norvitamin D derivative and novel20-epi-19-norvitamin D derivative.

Extensive studies have been made by the inventors to solve the problemsdescribed above. As a result, we have succeeded in synthesis of a novel2,2-disubsututed-19-norvitamin D derivative and a novel20-epi-19-norvitamin D derivative and have completed the presentinvention.

According to the present invention, there is provided a compoundrepresented by the general formula (I):

(wherein, R1 and R2 may be the same or different each other and theyrepresent a halogen atom or a hydroxyl group or an unsubstitutedstraight chain or branched chain alkyl group having 1-10 carbon atoms,or a substituted straight chain or branched chain alkyl group having1-10 carbon atoms, or an unsubstituted straight chain or branched chainalkenyl group having 2-15 carbon atoms, or a substituted straight chainor branched chain alkenyl group having 2-15 carbon atoms, or R1 may formtogether with R2 an unsubstituted spiro-cyclic alkyl group having 3-6carbon atoms, or a substituted spiro-cyclic alkyl group having 3-6carbon atoms, or an unsubstituted spiro-hetero-cyclic containing anoxygen atom as a hetero atom having 3-6 carbon atoms, or a substitutedspiro-hetero-cyclic containing an oxygen atom as a hetero atom having3-6 carbon atoms;

A represents a hydrogen or an unsubstituted straight chain or branchedchain alkyl group having 1-12 carbon atoms, or a substituted straightchain or branched chain alkyl group having 1-12 carbon atoms, or anunsubstituted straight chain or branched chain alkyloxy group having1-12 carbon atoms, or a substituted straight chain or branched chainalkyloxy group having 1-12 carbon atoms, or an unsubstituted straightchain or branched chain alkenyl group having 2-14 carbon atoms, or asubstituted straight chain or branched chain alkenyl group having 2-14carbon atoms.)

Preferably, in the general formula (I), R1 and R2 may be the same ordifferent each other and they represent a halogen atom or a hydroxylgroup or an unsubstituted straight chain or branched chain alkyl grouphaving 1-8 carbon atoms, or a straight chain or branched chain alkylgroup having 1-8 carbon atoms having at least one substituent selectedfrom the group consisting of a halogen atom, an unsubstituted straightchain or branched chain alkyloxy group having 1-4 carbon atoms, and arylgroup, amino group and azido group, or an unsubstituted straight chainor branched chain alkenyl group having 2-8 carbon atoms, or a straightchain or branched chain alkenyl group having 2-8 carbon atoms having atleast one substituent selected from the group consisting of a halogenatom, an unsubstituted straight chain or branched chain alkyloxy grouphaving 1-4 carbon atoms, and aryl group, amino group and azido group; orR1 may form together with R2 an unsubstituted spiro-cyclopropyl group ora spiro-cyclopropyl group substituted by at least one unsubstitutedstraight or branched hydroxyalkyl group having 1-4 carbon atoms, or anunsubstituted spiro-oxirane, or a spiro-oxirane group substituted by anunsubstituted straight or branched hydroxyalkyl group having 1-4 carbonatoms; A represents a straight chain or branched chain alkyl grouphaving 1-12 carbon atoms substituted by at least one hydroxy group, or astraight chain or branched chain alkyloxy group having 1-12 carbon atomssubstituted by at least one hydroxy group, or a straight chain orbranched chain alkenyl group having 2-14 carbon atoms substituted by atleast one hydroxy group.

Further preferably, in the general formula (I), R1 and R2 may be thesame or different each other and they represent a halogen atom, or ahydroxyl group, or an unsubstituted straight chain or branched chainalkyl group having 1-6 carbon atoms, or a straight chain or branchedchain alkyl group having 1-6 carbon atoms having at least onesubstituent selected from the group consisting of a halogen atom, anunsubstituted straight chain or branched chain alkyloxy group having 1-3carbon atoms, phenyl group, amino group and azido group, or anunsubstituted straight chain or branched chain alkenyl group having 2-4carbon atoms; or R1 may form together with R2 an unsubstitutedspiro-cyclopropyl group, or spiro-cyclopropyl group substituted by atleast one unsubstituted straight chain or branched chain hydroxyalkylgroup having 1-3 carbon atoms, or unsubstituted spiro-oxirane; Arepresents a hydrogen, or a straight chain or branched chain alkyl grouphaving 3-10 carbon atoms substituted by at least one hydroxy group, or astraight chain or branched chain alkyloxy group having 3-8 carbon atomssubstituted by at least one hydroxyl group, or a straight chain orbranched chain alkenyl group having 4-12 carbon atoms substituted by atleast one hydroxy group.

Further preferably, in the general formula (I), R1 and R2 may be thesame or different each other and they represent a hydroxyl group, or anunsubstituted straight or branched chain alkyl group having 1-6 carbonatoms, or a straight or branched chain alkyl group having 1-6 carbonatoms having at least one substituent selected from the group consistingof a fluorine atom and an unsubstituted straight chain or branched chainalkyloxy group having 1-3 atoms; or R1 may form together with R2 anunsubstituted spiro-oxirane; A represents a hydrogen atom, or a straightor branched chain alkyl group having 5-7 carbon atoms substituted by atleast one hydroxy group.

In the general formula (I), the configuration at 20-position may beS-configuration or R-configuration.

According to another aspect of the present invention, there is provideda compound represented by the general formula (IV);

(wherein, one of R4 and R5 represents a hydrogen atom and the otherrepresents a straight chain or branched chain alkyl group having 1-4carbon atoms substituted by a hydroxy group or —OR6 (wherein, R6represents a straight chain or branched chain alkyl group having 1-4carbon atoms substituted by a hydroxy group); or R4 may form ═CR7together with R5 (wherein, R7 represents a straight chain or branchedchain alkyl group having 1-4 carbon atoms substituted by a hydroxygroup).)

According to further aspect of the present invention, there is provideda pharmaceutical composition comprising a compound represented by thegeneral formula (I) or the general formula (IV) described above and apharmaceutically allowable carrier or a diluent.

According to still further aspect of the present invention, there isprovided a method of therapy or prevention of disease accompanyingabnormality in cell differentiation comprising a step of administratinga compound illustrated by the general formulae (I) or (IV) intherapeutic effective amount to an object demanding such therapy orprevention.

According to still further aspect of the present invention, there isprovided use of a compound illustrated by the general formulae (I) or(IV) described above for a pharmaceutical composition for therapy ofdisease accompanying abnormality in cell differentiation.

According to still further aspect of the present invention, there isprovided a method of preparing a compound represented by the generalformulae (I) described above comprising a step of obtaining a compoundrepresented by the general formula (III);

(wherein, Z may be the same or different each other and it represents ahydrogen atom or a protective group; Ph is a phenyl group), from acompound represented by the general formula (II);

(wherein, Z may be the same or different each other and it represents ahydrogen atom or a protective group.)

PREFERRED MODE OF CARRYING OUT THE INVENTION

The contents of the specification of Japanese Patent Application No.2002-297366 and Japanese Patent Application No. 2003-024183 on which thepriority right for the present application is claimed are incorporatedin their entirety by reference.

Detailed modes and methods with respect to vitamin D derivativesrepresented by the general formulae (I) and (IV) of the presentinvention are described below.

In this invention, “vitamin D derivative” is defined as a compoundhaving 9,10-seco-5,7,10 (19)-cholestatriene structure. In thisinvention, “19-nor-1,25-dihydroxyvitamin D derivative” is defined as acompound in which a 10 (19)-exo-methylene group is removed from acompound having 9,10-seco-5,7,10 (19)-cholestatriene structure.

A “halogen atom” for R1 and R2 in the general formula (I) is fluorine,chlorine, bromine and iodine, but fluorine may be preferable.

An “unsubstituted straight chain or branched chain alkyl group” for R1and R2 in the general formula (I) is preferably an unsubstitutedstraight chain or branched chain alkyl group having 1-10 carbon atoms,more preferably that-having 1-8 carbon atoms, more further preferablythat having 1-6, and still more further preferably that having 1-4. Thenon-limiting examples thereof includes a methyl group, ethyl group,n-propyl group, i-propyl group, n-butyl group, s-butyl group, i-butylgroup, t-butyl group, and a straight chain and branched chain pentylgroup, hexyl group, heptyl group, octyl group, nonyl group, decanylgroup.

A “substituted straight chain or branched chain alkyl group” for R1 andR2 in the general formula (I) means a group obtained by substituting oneor more hydrogen atoms of the “unsubstituted straight chain or branchedchain alkyl group” described above. A substituent in this case may be,for example, a halogen atom such as a fluorine atom, substitutedstraight chain or branched chain alkyloxy group (1-4 carbon atomspreferable, and 1-3 carbon atoms specifically preferable), unsubstitutedstraight chain or branched chain alkyloxy group (1-4 carbon atomspreferable, and 1-3 carbon atoms specifically preferable), unsubstitutedaryl group such as phenyl group, an aryl group (such as tolyl group)substituted by a halogen atom or an unsubstituted straight chain orbranched chain alkyl group having 1-4 carbon atoms, an amino group, anazido group, and the like. Further a substituent in this case may bespecifically preferably a fluorine atom, a methoxy group, an ethoxygroup, a phenyl group, an amino group, an azido group, and the like.

An “unsubstituted straight chain or branched chain alkenyl group” for R1and R2 is preferably a straight chain or branched chain alkenyl grouphaving 2-15 carbon atoms having at least one double bond. Number ofcarbon atoms in this case is preferably 2-8, more preferably 2-6, andstill more preferably 2-4. Number of double bond in this case ispreferably 1-3, more preferably 1 or 2, and still more preferably 1. A“substituted straight chain or branched chain alkenyl group” means agroup obtained by substituting one or more hydrogen atoms of the“unsubstituted straight chain or branched chain alkyl group” describedabove. A substituent in this case may be, for example, a halogen atom orunsubstituted straight chain or branched chain alkyl group having 1-4carbon atoms.

The configuration at 2-position may be R-configuration orS-configuration.

An “unsubstituted spiro-cyclic alkyl group” which R1 forms together withR2 may preferably have 3-6 carbon atoms, more preferably 3-4 carbonatoms, and a spiro-cyclopropyl group specifically preferable.

A “substituted spiro-cyclic alkyl group” means a group obtained bysubstituting one or more hydrogen atoms of the above-described“unsubstituted spiro-cyclic alkyl group”. A substituent in this case ispreferably an unsubstituted straight chain or branched chainhydroxyalkyl. Number of carbon atoms in this case is preferably 1-4,more preferably 1-3. Such a substituent may be, for example, ahydroxymethyl group, hydroxyethyl group, hydroxypropyl group, and thelike.

An “unsubstituted spiro-hetero-cyclic containing an oxygen atom as ahetero atom” which R1 forms together with R2 may preferably have 3-6carbon atoms, more preferably 3-4 carbon atoms. It may preferably haveone oxygen atom as a hetero atom. Spiro-oxirane may be specificallypreferable.

A “substituted spiro-hetero cyclic containing an oxygen atom as a heteroatom” means a group obtained by substituting one or more hydrogen atomsof the “unsubstituted spiro-hetero cyclic containing an oxygen atom as ahetero atom” described above.

An “unsubstituted straight chain or branched chain alkyl group” for A ofthe general formula (I) is preferably unsubstituted straight chain orbranched chain alkyl group having 1-12 carbon atoms. Number of carbonatom in this case is preferably 3-10, more preferably 5-7, still morepreferably 6. The non-limiting example thereof may be a methyl group,ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butylgroup, i-butyl group, t-butyl group, and a straight chain and branchedchain pentyl group, hexyl group, heptyl group, octyl group, nonyl group,decanyl group.

A “substituted straight chain or branched chain alkyl group” for A meansa group obtained by substituting one or more hydrogen atoms of the“unsubstituted straight chain or branched chain alkyl group” describedabove. A substituent in this case is preferably a hydroxy group.Non-limiting number of the substituent is preferably 1-3, morepreferably 1 or 2. Such a substituent may be, for example, ahydroxymethyl group, hydroxyethyl group, hydroxybutyl group,hydroxypropyl group, hydroxypentyl group, hydroxyhexyl group,hydroxyheptyl group, hydroxyoctyl group, hydroxynonyl group,hydroxydecanyl group, 4-hydroxy-4-methylpentyl group,1,4-dihydroxy-4-methylpentyl group, 4-ethyl-4-hydroxyhexyl group,6-hydroxy-6-methyl-2-heptyl group, 7-hydroxy-7-methyl-2-octyl group,5,6-dihydroxy-6-methyl-2-heptyl group, and the like.

An “unsubstituted straight chain or branched chain alkyloxy group” for Aof the general formula (I) is preferably an unsubstituted straight chainor branched chain alkyloxy group having 1-12 carbon atoms. Number ofcarbon atom in this case is preferably 3-8, more preferably 4-6, stillmore preferably 5. The non-limiting example thereof is preferably amethoxy group, an ethoxy group, a propoxy group, a butoxy group, apentyloxy group, a hexyloxy group, and the like.

A “substituted straight chain or branched chain alkyloxy group” for Ameans a group obtained by substituting one or more hydrogen atoms of the“unsubstituted straight chain or branched chain alkyloxy group”described above. A substituent in this case is preferably a hydroxygroup. Non-limiting number of the substituent is preferably 1-3, andmore preferably 1 or 2. For example, —OC₂H₄C(CH₃)₂OH,—OCH₂CHOHC(CH₃)₂OH, and the like.

An “unsubstituted straight chain or branched chain alkenyl group” for Aof the general formula (I) is preferably an unsubstituted straight chainor branched chain alkenyl group having 2-14 carbon atoms. Number ofcarbon atom in this case is preferably 4-12, more preferably 5-10 andmost preferably 6-9. As a double bond may be cis- or trans-. Number ofthe double bond may be preferably 1-3 and more preferably 1 or 2. Thenon-limiting examples thereof may be preferably a vinyl group, propenylgroup, butenyl group, hexenyl group, heptenyl group, octenyl group,nonenyl group, decanenyl group, 4-methyl-penta-1-ene-1-yl group,5-ethyl-1,3-hepta-1,3-diene-1-yl group, and the like.

A “substituted straight chain or branched chain alkenyl group” for Ameans a group obtained by substituting one or more hydrogen atom of the“unsubstituted straight chain or branched chain alkenyl group” describedabove. As a substituent in this case is preferably a hydroxy group.Non-limiting number of the substituent is preferably 1-3, and morepreferably 1 or 2. For example, 4-hydroxy-4-methyl-penta-1-ene-1-ylgroup (—C₂H₂CH₂C(CH₃)₂OH), 5-hydroxy-5-ethyl-hepta-1,3 -diene-1-yl group(—C₄H₄C(C₂H₅)₂OH), and the like.

The configuration of the hydroxy groups at the 1- and 3-positions in thecompound of formula (I) of the present invention can occur in α or βconformation, and the respective compounds are all included within thescope of the present invention. Furthermore, cis- and trans-geometricalisomers of the compound of formula (I) wherein A is alkenyl groupresulting from the double bond, and other optical and geometricalisomers are all included within the scope of the present invention.

Examples of the compound of the general formula (I) of the presentinvention are as follows:

As a “straight chain or branched chain alkyl group having 1-4 carbonatoms” of “straight chain or branched chain alkyl group having 1-4carbon atoms substituted by a hydroxy group” of the definition on R4 orR5 of the general formula (IV) is preferably a methyl group, ethylgroup, n-propyl group, i-propyl group, n-butyl group, s-butyl group,i-butyl group, t-butyl group, and the like, more preferably a straightchain or branched chain alkyl group having 2-3 carbon atoms, and morepreferably an ethyl group, n-propyl group. Number of a hydroxy group tobe substituted is preferably 1 or 2, and more preferably 1.

As a “straight chain or branched chain alkyl group having 1-4 carbonatoms” of “straight chain or branched chain alkyl group having 1-4carbon atoms substituted by a hydroxy group” of the definition on R6 ofthe general formula (IV) is preferably a methyl group, ethyl group,n-propyl group, i-propyl group, n-butyl group, s-butyl group, i-butylgroup, t-butyl group, and the like, more preferably a straight chain orbranched chain alkyl group having 1-3 carbon atoms, and more preferablya methyl group, ethyl group, n-propyl group, still more preferably anethyl group. Number of a hydroxy group to be substituted is preferably 1or 2, and more preferably 1.

As a “straight chain or branched chain alkyl group having 1-4 carbonatoms” of “straight chain or branched chain alkyl group having 1-4carbon atoms substituted by a hydroxy group” of the definition on R7 ofthe general formula (IV) is preferably a methyl group, ethyl group,n-propyl group, i-propyl group, n-butyl group, s-butyl group, i-butylgroup, t-butyl group, and the like, and more preferably a straight chainor branched chain alkyl group having 1-3 carbon atoms, and morepreferably a methyl group, ethyl group, ethyl group-and still morepreferably a methyl group. Number of a hydroxy group to be substitutedis preferably 1 or 2, and more preferably 1.

In the case where one of R₄ and R₅ of the general formula (IV) is ahydrogen atom and the other of the two is a straight chain or branchedchain alkyl group having 1-4 carbon atoms substituted by a hydroxy groupor —OR₆, the straight chain or branched chain alkyl group having 1-4carbon atoms substituted by a hydroxy group and —OR₆ may be situated at2α-position or 2β-position.

In the case where R₄ forms ═CR₇ together with R₅, each of (Z) form or(E) form produced by this double bond may be preferable.

Examples of the compound of the general formula (IV) are as follows:

The vitamin D derivatives represented by the general formula (I) or (IV)of the present invention can be used as active ingredients ofpharmaceutical compositions (such as a cell differentiation regulatingagent).

The compounds of the present invention are preferably formulated intoappropriate dosage forms with pharmaceutically acceptable carriers,excipients, disintegrants, lubricants, binders, flavors, colorants, andthe like. Examples of the dosage forms include tablets, granules, finegranules, capsules, powder, injections, solutions, suspensions,emulsions, percutaneous administration formulations, suppositories andthe like.

There is no restriction for routes of administration for the compoundsof the present invention. The compounds may be administered orally orparenterally (intravenously,. intramuscularly, intraperitoneally,percutaneously and the like).

Dosage of compounds of the present invention can be appropriately chosendepending on target disease, conditions, body type, constitution, ageand sex of the patient, administration route, dosage form and otherfactors. Typically, the lower limit of the dosage for an adult rangesfrom 0.001 μg to 0.1 μg and preferably around 0.01 μg daily, and theupper limit of the dosage for an adult ranges from 100 μg to 10000 μgand preferably from 200 μg to 1000 μg, which may be administered individed portion once to three times a day.

The vitamin D derivative of the general formula (I) is a novel compound,and there is no limitation with respect to methods of synthesis of thecompound. It can be synthesized by a method comprising a step ofobtaining a compound represented by the general formula (III):

(wherein, Z may be the same or different each other and hydrogen or aprotective group, Ph is a phenyl group) from a compound represented bythe general formula (II):

(wherein, Z may be the same or different each other and hydrogen or aprotective group.)

A protective group as Z may be the same or different each other and maybe a substituted silyl group, an acyl group, an alkyl group which may bepossibly substituted, more preferably a benzyl group, trimethylsilylgroup, t-butyldimethylsilyl group, and the like.

The protective group can be removed by a conventional process well-knownto a chemical field at a proper step in the synthesis.

The vitamin D derivatives of the general formula (I) can be synthesizedby, for example, a method described below:

A general synthesis scheme of A-ring phosphine oxide of the presentinvention is as follows:

A cyclohexanone derivative (compound B) having a hydroxy group protectby a silyl group as a starting material can be synthesized from(−)-quinic acid by a well-known method (Perlman, K. L., Sewnson, R. E.,Paaren, H. E., Schnoes, H. K., DeLuca, H. F., Tetrahedron Lett., 1991,32, 7663-7666). The cyclohexanone derivative B is once changed to analcoholic form C by a reducing agent such as sodium boron hydride. Then,a hydroxy group of the alcoholic form C is protected by a protectivegroup and to form a compound D. It is preferable to from an etherlinkage by the use of a benzyl group as a protective group. Next, only aprotect of a trimethylsilyl group at 4-position of the compound D isremoved by acid treatment using such as acetic acid, and changed to aketone group by oxidation-reaction using such as dimethylsulfoxide andoxalyl dichloride, to obtain a compound F. A ketone group of thecompound F is changed to methylene by Wittig reagent to obtain acompound G. Compound G thus obtained is changed to a spiro-epoxycompound H by a peroxidizing agent such as m-chloroperbenzoic acid. Abenzyl protective group at 6-position is removed by hydrogenationreaction by palladium catalyst to form a compound I. A hydroxy groupformed is oxidized to a ketone group to form a compound J. Thereafter,the compound J thus formed is changed to an alcoholic form L bycarbon-addition and reduction-reaction by (trimethylsilyl) acetic ester.The alcoholic form L is diphenylphosphinized and oxidized by hydrogenperoxide to obtain an objective A-ring phosphine oxide compound M.

CD-ring 25-hydroxy Grundmann's ketone can be synthesized by ozonolysisof vitamin D derivative having desired CD-ring known by reference(Sandina, F. J., Mourino, S., Castedo, L., J. Org. Chem., 1986, 51,1264-1269.: Kiegiel, J., Wovkulich, P. M., Uskokovic, M. R., TetrahedronLett., 1991, 32, 6057-6060.: Fernadez, B., Perez, J. A., Granja, J. R.,Castefo, L., Mourino, A., J. Org. Chem., 1992, 57,3173-3178.: Fujishima,T., Konno, K., Nakagawa, K., Kurobe, M., Okano, T., Takayama, H.,Bioogr. Med. Chem., 2000, 8, 123-134.)

Synthesis of desired vitamin D derivative can be carried out by bondingA-ring phosphine oxide compound with CD-ring 25-hydroxy Grundmann'sketone which is synthesized in such a manner as described above.Generally, when the coupling reaction is carried out without protectinga hydroxy group at 25-position, yield is lowered. It is, therefore,preferable to protect a hydroxy group at 25-position of 25-hydroxyGrundmann's ketone by a proper protective group such as acyl group,substituted silyl group, substituted alkyl group, and the like (forexample, triethylsilyl group, methoxymethyl group, and the like). A-ringphosphine oxide compound is treated with strong base such as butyllithium to form phosphinoxycarbanion which is reacted with a ketonegroup of CD-ring Grundmann's ketone.

Spiro-oxirane at 2-position is optionally subjected to ring cleavage toform 2,2-disubstituted one. For example, when a fluorinating agent suchas tetrabutylammonium fluoride is used, a derivative having afluoromethyl group and a hydroxy group at 2-position can be synthesized.When a metal hydrogenating agent such lithium aluminum hydride is used,a derivative having a methyl group and a hydroxy group at 2-position canbe synthesized. When a metylating agent or methoxizating agent is used,a derivative having a methyl group and a hydroxy group, or a derivativehaving a methoxymethyl group and a hydroxy group can be synthesized,respectively.

The vitamin D derivative represented by the general formula (IV) of thepresent invention is a novel compound and there is no limitation withrespect to methods of synthesis thereof. It can be synthesized by amethod described in the general synthesis scheme described below:

As shown in the scheme described above, the known vitamin D derivativehaving a desired CD-ring is subjected to ozonolysis, 20-position of20-aldehyde is epimerized by DBU, and then immediately reducing by NaBH₄to obtain CD-ring 20-epi-25-hydroxy Grundmann's ketone as a main product(non-natural type-22-alcoholic form) (Sandina, F. J., Mourino, S.,Castedo, L., J. Org. Chem., 1986, 51, 1264-1269.: Kiegiel, J.,Wovkulich, P. M., Uskokovic, M. R., Tetrahedron Lett., 1991, 32,6057-6060.: Fernadez, B., Perez, J. A., Granja, J. R., Castefo, L.,Mourino, A., J. Org. Chem., 1992, 57, 3173-3178.: Fujishima, T., Konno,K., Nakagawa, K., Kurobe, M., Okano, T., Takayama, H., Bioogr. Med.Chem., 2000, 8, 123-134.).

EXAMPLES

The present invention will be described specifically by way of thefollowing Examples, which is no way limit the invention.

(Conditions for Instrumental Analysis)

¹H NMR and ¹⁹F MHR were measured with a Bruker ARX-400 spectrometer.Chemical shifts were shown in terms of δ value using tetramethylsilane(TMS) as an internal standard, and trifluorotoluene as an externalstandard (δ=−63 ppm) for ¹⁹F NMR. NMR spectra were described using thefollowing abbreviations: s=singlet, d=doublet, t=triplet, m=multiplet,arom=aromatic, br=broad signal.

MS spectra were measured by electronic ionization (EI) method with JEOLJMS-AX505HA spectrometer. In the specification, “no M⁺” means that no M⁺was observed. “HR-MS” stands for High Resolution MS spectrum.

UV spectra were obtained on a Beckmann DU-7500 spectrophotometer.

Mixtures of some isomers were separated and refined with HPLC systemequipped with JASCO MD-910 multiwavelength UV detector.

All reactions, unless specifically mentioned, were conducted under anatmosphere of argon gas.

Wakogel C-200 was used as a silica gel.

In following experiments, the numbering of the compounds 2-13, 30-38,118, 119, 125-135 corresponding to the A-ring of the 19-norvitamin Dwere expressed based on the IUPAC nomenclature of organic chemistry. Thenomenclature of the compounds having 19-norvitamin D structure afterbeing bonded with CD-ring grundmann keton was expressed on the basis ofthe steroidal numbering.

Example 1 (1,4-cis)- and(1,4-trans)-3,5-bis-[(t-butyldimethylsilyl)oxy]-4-[(trimethylsilyl)oxy]-cyclohexanols(Compound 3)

Sodium borohydride (NaBH₄, 217.5 mg, 5.75 mmol) was added over a periodof about 10 min to a solution of(3R,5R)-3,5-bis-[(t-butyldimethylsilyl)oxy]-4-[(trimethylsilyl)oxy]-cyclohexanone(Compound 2) (5.13 g, 11.5 mmol) in ethanol (EtOH, 50 mL) cooled to 0°C. Stirring was continued for 1.5 h, and then ice water was added to thereaction mixture. After extraction with ethyl acetate (AcOEt), theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate (MgSO₄), and the solvent was distilled off. Theresidue was purified by silica gel column chromatography (60 g; 5%AcOEt/hexane), to yield Compound 3 (5.15 g, 99%) as a mixture of 1,4-cisisomer and 1,4-trans isomer. The ratio of the stereoisomers constitutingthe mixture was ca. 2:1. It was impossible to know whether the majorproduct was 1,4-cis isomer or 1,4-trans isomer. In this connection, theC-1 position is pseudoasymmetric, and 1,4-cis isomer and 1,4-transisomer are achiral diastereoisomers to each other.

2: ¹H NMR (CDCl₃) δ: 0.05 (6H, Si-Me×2), 0.06, 0.07 (each 3H, s,Si-Me×2), 0.16 (9H, s, SiMe₃), 0.86, 0.89 (each 9H, s, Si-tBu×2), 2.17(1H, m), 2.36 (1H, dd, J=13.7, 4.5 Hz), 2.73 (2H, m), 3.80 (1H, m, H-4),4.03 (1H, dd, J=8.3, 2.3 Hz, H-5), 4.24 (1H, ddd, J=10.6, 4.5, 2.3 Hz,H-3). MS m/z (%): no M⁺, 431 (3), 389 (68), 299 (69), 257 (44), 73(100).

3: ¹H NMR (CDCl₃) δ: 0.06-0.11 (12H, Si-Me×4), 0.11, 0.12 (9H, s,SiMe₃), 0.89-0.91 (18H, s, Si-tBu×2), 1.52-1.92 (4H, m), 3.43, 3.68 (ca.2:1) (1H, m), 3.94-4.22 (3H, m). MS m/z (%): no M⁺, 391 (3), 373 (15),301 (19), 259 (23), 73 (100).

Example 2 (1,4-cis)- and(1,4-trans)-3,5-bis-[(t-butyldimethylsilyl)oxy]-4-[(trimethylsilyl)oxy]-cyclohexanolbenzyl ethers (Compound 4)

To a solution of Compound 3 (a mixture of ca. 2:1 of the major productand the minor product; 4.57 g, 10.2 mmol) in dry dimethylformamide (DMF,30 mL) cooled to 0° C. were added sodium hydride (NaH, 1.22 g, 30.5mmol, 60% paraffin liquid) and benzyl bromide (3.483 g, 20.4 mmol), andstirred for 8 h. Ice water was added to the reaction mixture, and thenthe reaction mixture was extracted with AcOEt/hexane (1:1). The organiclayer was washed with saturated brine and dried over anhydrous MgSO₄,and the solvent was distilled off. The residue was purified by silicagel column chromatography (150 g; 3% AcOEt/hexane), to yield Compound 4(4.66 g, 85%) as a mixture of 1,4-cis isomer and 1,4-trans isomer. Theratio of the stereoisomers constituting the mixture was ca. 2:1. It wasimpossible to know whether the major product was 1,4-cis isomer or1,4-trans isomer. In this connection, the C-1 position ispseudoasymmetric, and 1,4-cis isomer and 1,4-trans isomer are achiraldiastereoisomers to each other.

4a (major product): ¹H NMR (CDCl₃) δ: 0.03, 0.06 (each 6 EL Si-Me×4),0.10 (9H, s, SiMe₃), 0.85, 0.90 (each 9H, s, Si-tBu×2), 1.70-1.93 (4H,m), 3.57 (1H, m), 3.64 (1H, tt, J=11.0, 5.0 Hz), 3.80 (1H, m), 3.91 (1H,ddd, J=9.5, 4.3, 2.4 Hz), 4.51, 4.55 (each 1H, d, J=11.7 Hz, PhCH ₂),7.30-7.37 (5H, m, arom-H).

4b (minor product): ¹H NMR (CDCl₃) δ: 0.01, 0.046 (each 3H, Si-Me×2),0.055 (6H, s, Si-Me×2), 0.11 (9H, s, SiMe₃), 0.84, 0.88 (each 9H, s,Si-tBu×2), 1.37 (2H, m), 2.07 (1H, m), 2.19 (1H, m), 3.28 (1H, dd,J=8.5, 2.3 Hz), 3.80 (2H, m), 3.93 (1H, m), 4.50, 4.52 (each 1H, d,J=12.1 Hz, PhCH ₂), 7.30-7.37 (5H, m, arom-H). MS m/z (%) of themixture: no M⁺, 481 (5), 391 (9), 373 (20), 349 (6), 259 (6), 91 (100).

Example 3 (1,4-cis)- and(1,4-trans)-2,6-bis-[(t-butyldimethylsilyl)oxy]-4-[(benzyl)oxy]-cyclohexanols(Compound 5)

Compound 4 (a mixture of ca. 2:1 of Compound 4a and Compound 4b; 269 mg,0.499 mmol) was dissolved in a mixture of tetrahydrofuran (THF), aceticacid (AcOH) and water (8.5 mL; 8:8: 1, v/v/v), and stirred for 20 h atroom temperature. The reaction mixture was diluted with AcOEt, andsuccessively washed with 5% sodium hydrogencarbonate (NaHCO₃) aqueoussolution and saturated brine. The organic layer was dried over anhydroussodium sulfate (Na₂SO₄). The solvent was distilled off, and the residuewas purified by silica gel column chromatography (15 g; 4%AcOEt/hexane), to give Compound 5 (187 mg, 80%) as a mixture of 1,4-cisisomer and 1,4-trans isomer. The ratio of the stereoisomers constitutingthe mixture was ca. 2:1. It was impossible to know whether the majorproduct was 1,4-cis isomer or 1,4-trans isomer. In this connection, the.C-1 position is pseudoasymmetric, and 1,4-cis isomer and 1,4-transisomer are achiral diastereoisomers to each other.

5a (major product, more polar): ¹H NMR (CDCl₃) δ: 0.04 (6H, s, Si-Me×2),0.07, 0.08 (each 3H, Si-Me×2), 0.84, 0.90 (each 9H, s, Si-tBu×2),1.60-1.73 (2H, m), 1.89 (1H, m), 1.98 (1H, m), 2.43 (1H, s, OH), 3.57(1H, t, J=3.2 Hz, H-4), 3.69 (1H, tt, J=11.4, 4.1 Hz, H-1), 3.96 (1H,ddd, J=11.6, 4.8, 3.2 Hz), 4.10 (1H, m), 4.54 (2H, s, PhCH ₂), 7.30-7.35(5H, m, arom-H).

5b (minor product, less polar): ¹H NMR (CDCl₃) δ: 0.057, 0.076, 0.077,0.091 (each 3H, Si-Me×4), 0.86, 0.90 (each 9H, s, Si-tBu×2), 1.36-1.47(2H, m), 2.01 (1H, d, J=5.7 Hz, OH), 2.13 (1H, m), 2.22 (1H, m), 3.28(1H, ddd, J=8.7, 5.7, 2.9 Hz, H-4), 3.75 (2H, m, H-1, 5), 4.13 (1H, m,H-3), 4.50, 4.54 (each 1H, d, J=11.8 Hz, PhCH ₂), 7.30-7.35 (5H, m,arom-H). MS m/z (%) of the mixture: no M⁺, 409 (6), 319 (2), 301 (17),277 (6), 259 (4), 211 (9), 1.69 (31), 91 (100).

Example 4(2R,6R)-2,6-bis-[(t-butyldimethylsilyl)oxy]-4-[(benzyl)oxy]-cyclohexanone(Compound 6)

To a solution of oxalyl chloride (384 μL, 4.40 mmol) in dry methylenechloride (CH₂Cl₂, 5 mL) cooled to −78° C. was added a solution ofdimethyl sulfoxide (DMSO, 621 μL, 8.75 mmol) in dry CH₂Cl₂ (2.5 mL), andstirred for 5 min. To this cooled stirring solution, a solution ofCompound 5 (1.71 g, 3.66 mmol, a mixture of isomers 5a:5b=ca. 2:1) indry CH₂Cl₂ (10 mL) was added. The reaction mixture was stirred for 15min, and triethylamine (Et₃N, 2.55 mL, 18.3 mmol) was added to thereaction mixture. The mixture was stirred while gradually raising thereaction temperature from −78° C. to room temperature, over a period ofca. 1.5 h. Then the reaction solution was poured into ice water, andthen extracted with CH₂Cl₂. The organic layer was washed with saturatedbrine, and dried over anhydrous MgSO₄. The solvent was removed byevaporation. The residue was purified by silica gel columnchromatography (30 g; 5% AcOEt/hexane), to yield Compound 6 (1.69 g,99%) as a single compound.

¹H NMR (CDCl₃) δ: 0.02, 0.03, 0.06, 0.12 (each 3H, Si-Me×4), 0.86, 0.90(each 9H, s, Si-tBu×2), 1.74 (2H, m), 2.31 (1H, m), 2.51 (1H, m), 4.12(2H, m), 4.55, 4.60 (each 1H, d, J=11.7 Hz, PhCH ₂), 4.73 (1H, dd,J=12.1, 6.4 Hz), 7.27-7.35 (5H, m, arom-H). MS m/z (%): no M⁺, 449 (2),407 (27), 299 (21), 275 (5), 91 (100).

Example 5(3R,5R)-3,5-bis-[(t-butyldimethylsilyl)oxy]-4-methylene-cyclohexanolbenzyl ether (Compound 7)

To a suspension of methyltriphenylphosphonium bromide (1.55 g, 4.34mmol) in dry THF (10 mL) cooled to 0° C. was added n-butyl lithium(n-BuLi, 2.71 mL, 4.34 mmol, 1.6 M solution in hexane), and the mixturewas stirred for 10 min, and further stirred for 1 h at room temperature.To the resulting orange mixture was added over ca. 20 min period asolution of Compound 6 (1.0 g, 2.15 mmol) dissolved in dry THF (10 mL).After being stirred for 1 h at 0° C. and for 17 h at room temperature,the reaction mixture was poured into ice water, and extracted withAcOEt. The organic layer was rinsed with saturated brine, and dried overanhydrous MgSO₄. The solvent was removed by evaporation. The residue waspurified by silica gel column chromatography (5 g; 2% AcOEt/hexane), toyield Compound 7 (978.5 mg, 98%, single compound).

¹H NMR (CDCl₃) δ: −0.01, 0.04, 0.06, 0.07 (each 3H, Si-Me×4), 0.84, 0.92(each 9H, s, Si-tBu×2), 1.35-1.46 (2H, m), 2.18 (1H, m), 2.35 (1H, m),3.94 (1H, tt, J=11.2, 4.2 Hz, H-1), 4.40-4.46 (2H, m, H-1, 3), 4.54,4.56 (each 1H, d, J=11.9 Hz, PhCH ₂), 4.84 (1H, m, C═CH), 5.03 (1H, t,J=2.0 Hz, C═CH), 7.27-7.35 (5H, m, arom-H). MS m/z (%): no M⁺, 405 (84),355 (2), 313 (35), 297 (15), 273 (20), 223 (18), 165 (22), 91 (100).

Example 6 (3,6-cis)- and(3,6-trans)-6-benzyloxy-4,8-bis-[(t-butyldimethylsilyl)oxy]-1-oxa-spiro[2.5]octanes(Compound 8)

To a solution of Compound 7 (191.4 mg, 0.414 mmol) in CH₂Cl₂ (2 mL)cooled to 0° C. was added m-chloroperbenzoic acid (106.8 mg, 0.619mmol). The reaction mixture was stirred for 2 h at 0° C. and for 16 h atroom temperature, and then CH₂Cl₂ was added thereto. The CH₂Cl₂ layerwas successively washed with 5% NaHCO₃ and saturated brine, and driedover anhydrous MgSO₄. The solvent was removed by evaporation, and theresidue was purified by silica gel column chromatography (8 g; 2%→5%AcOEt/hexane), to yield Compound 8b (19.0 mg) from 2% AcOEt-containinghexane eluate and Compound 8a (178.0 mg) from 5% AcOEt-containing hexaneeluate. The total yield was 99%. It was impossible to know whether themajor product was 3,6-cis isomer or 3,6-trans isomer.

8a (more polar isomer): ¹H NMR (CDCl₃) δ: 0.01, 0.02, 0.05, 0.06 (each3H, s, Si-Me×4), 0.85, 0.88 (each 9H, s, Si-tBu×2), 1.66-1.75 (2H, m),2.05 (1H, m), 2.24 (1H, m), 2.62, 3.03 (each 1H, d, J=5.3 Hz, CH₂O),3.53 (1H, t, J=3.0 Hz), 3.84 (1H, tt, J=11.1, 4.1 Hz, H-1), 4.21 (1H,dd, J=11.6, 4.4 Hz), 4.56 (2H, s, PhCH ₂), 7.27-7.35 (5H, m, arom-H). MSm/z (%): no M⁺, 421 (3), 391 (2), 313 (18), 91 (100), 75 (74).

8b (less polar isomer): ¹H NMR (CDCl₃) δ: 0.02 (6H, s, Si-Me×2), 0.04,0.07 (each 3H, s, Si-Me×4), 0.856, 0.863 (each 9H, s, Si-tBu×2),1.44-1.55 (2H, m), 2.18 (1H, m), 2.35-2.41 (1H, m), 2.38, 2.96 (each 1H,d, J=5.6 Hz, CH₂O), 3.55 (1H, m), 3.93 (1H, tt, J=11.2, 4.2 Hz, H-1),4.18 (1H, dd, J=11.5, 4.8 Hz), 4.54, 4.57 (each 1H, d, J=11.8 Hz, PhCH₂), 7.27-7.35 (5H, m, arom. H). MS m/z (%): no M⁺, 421 (7), 391 (3), 313(11), 91 (96), 75 (100).

Example 7 (3,6-cis)- and(3,6-trans)-4,8-bis-[(t-butyldimethylsilyl)oxy]-1-oxa-spiro[2.5]octane-6-oles(Compound 9)

To a solution of Compound 8a (216.8 mg, 0.453 mmol), which was an epoxycompound, in AcOEt (2 mL), was added 10% palladium on activated carbon(43.4 mg), and then the mixture was vigorously stirred with H₂ gas for 1h, under an atmospheric pressure, at room temperature. The reactionmixture was filtered through Celite, washed with ethanol and AcOEt, andthe combined filtrate was subjected to evaporation to remove thesolvent. The residue was purified by silica gel column chromatography (8g; 8% AcOEt/hexane), to obtain Compound 9a (176.0 mg, quantitative).

Catalytic hydrogenation and column purification of Compound 8b (24.6 mg,0.0514 mmol) were carried out in the same manner as described above, toobtain Compound 9b (17.2 mg, 86%), which was a debenzylated compound.

9a: ¹H NMR (CDCl₃) δ: 0.05, 0.07, 0.10, 0.15 (each 3H, s, Si-Me×4),0.87, 0.91 (each 9H, s, Si-tBu×2), 1.62 (1H, m), 1.80 (1H, t, J=14.1,2.9 Hz), 2.08, 2.27 (each 1H, m), 2.50, 2.95 (each 1H, d, J=5.5 Hz,CH₂O), 3.80 (1H, m), 4.14 (1H, m), 4.40 (1H, m). MS m/z (%): no M⁺, 331(25), 313 (52), 301 (16), 199 (63), 181 (46), 75 (100).

9b: ¹H NMR (CDCl₃) δ: 0.05, 0.07, 0.08, 0.09 (each 3H, s, Si-Me×4),0.88, 0.89 (each 9H), s, Si-tBu×2), 1.68, 1.82, 1.98, 2.14 (each 1H, m,H-2, 6), 2.71 (1H, m, CH₂O), 2.82 (1H, d, J=5.4 Hz, CH₂O), 4.00 (2H, m),4.21 (1H, m). MS m/z (%): no M⁺, 331 (20), 313 (42), 301 (14), 199 (72),181 (39), 73 (100).

Example 8(4R,8R)-4,8-bis-[(t-butyldimethylsilyl)oxy]-1-oxa-spiro[2.5]octane-6-one(Compound 10)

To a solution of oxalyl chloride (51 μL, 0.585 mmol) in dry methylenechloride (CH₂Cl₂, 0.5 mL) cooled to −78° C. was added a solution of DMSO(83 μL, 1.170 mmol) in dry CH₂Cl₂ (0.2 mL). After 5 min of stirring, asolution of Compound 9 (a mixture of Compounds 9a:9b=ca. 10:1) (190.6mg, 0.490 mmol) in dry CH₂Cl₂ (1.3 mL) was added.

The reaction mixture was stirred for 15 min at −78° C., and Et₃N (341μL, 2.445 mmol) was added. The whole mixture was stirred over a periodof about 1.5 h) until the reaction temperature was raised from −78° C.to room temperature. Ice water was added to the reaction mixture, andthe mixture was extracted with CH₂Cl₂. The organic layer was washed withsaturated brine, and dried over anhydrous MgSO₄. The solvent wasdistilled off. The residue was purified by silica gel columnchromatography (8 g; 5% AcOEt/hexane), to yield Compound 10 (188.5 mg,99%) as a single compound.

¹H NMR (CDCl₃) δ: 0.047, 0.055, 0.061, 0.086 (each 3H, s, Si-Me×4),0.86, 0.88 (each 9H, s, Si-tBu×2), 2.45 (1H, ddd, J=14.4, 7.9, 1.1 Hz),2.57 (1H) ddd, J=14.2, 6.2, 1.9 Hz), 2.67 (1H, ddd, J=14.2, 3.9, 1.1Hz), 2.79 (1H) ddd, J=14.4, 4.9, 1.1 Hz), 2.80, 3.02 (each 1H, d, J=5.3Hz, CH₂O), 4.03 (1H, d, J=6.2, 3.9 Hz), 4.21 (1H, dd, J=7.9, 4.9 Hz),4.40 (1H, m). MS m/z (%): no M⁺, 329 (31), 313 (10), 299 (9), 197 (20),75 (100).

Example 9 [(aS*,4R,8R)- and[(aR*,4R,8R)-[4,8-bis-[(t-butyldimethylsilyl)oxy]-1-oxa-spiro[2.5]octy-6-ylidene]-methylacetate esters (Compound 11)

To a solution of diisopropylamine (115 μL, 0.82 mmol) in dry THF (1 mL)cooled to −78° C. was added n-BuLi (513 μL, 0.82 mmol, 1.6 M solution inhexane) and stirred for 15 min. Then, methyl (trimethylsilyl)acetate(135 μL, 0.82 mmol) was added thereto. After 10 min of stirring, asolution of Compound 10 (158.8 mg, 0.41 mmol) dissolved in dry THF (1.2mL) was slowly added, and stirring was continued for 1 h at −78° C. Tothe reaction mixture was added saturated ammonium chloride (NH₄Cl)aqueous solution, and the mixture was extracted with AcOEt. The organiclayer was washed with saturated brine, dried over anhydrous MgSO₄, andevaporated to remove the solvent. The residue was purified by silica gelcolumn chromatography (8 g; 2% AcOEt/hexane), to give Compound 11 (172.1mg, 95%) as a mixture of two stereoisomers. The ratio of thestereoisomers constituting the mixture was ca. 3:1. It was impossible toknow whether the major product was aS*,4R,8R isomer or aR*,4R,8R isomer.

NMR Data of the Mixture

11a (major product): ¹H NMR (CDCl₃) δ: 0.03-0.08 (12H, Si-Me×4), 0.86,0.88 (each 9H, s, Si-tBu×2), 2.41 (1H, d, J=13.2, 6.7 Hz), 2.47 (1H, m),2.74 (1H, d, J=5.4 Hz, CH₂O), 2.80 (1H, dd, J=13.7, 7.6 Hz), 2.90 (1H,d, J=5.4 Hz, CH₂O), 3.40 (1H, dd, J=13.7, 4.0 Hz), 3.70 (3H, s, OMe),3.91 (2H, m, H-3, 5), 5.76 (1H, s, C═CHCO).

11b (minor product): ¹H NMR (CDCl₃) δ: 0.03-0.08 (12H, Si-Me×4), 0.86,0.88 (each 9H, s, Si-tBu×2), 2.28 (1H, m), 2.60 (1H, dd, J=13.2, 4.6Hz), 2.67 (1H, d, J=5.4 Hz, CH₂O), 2.72 (1H, m), 2.92 (1H, d, J=5.4 Hz,CH₂O), 3.48 (1H, m), 3.69 (3H, s, OMe), 3.80 (1H, dd, J=5.9, 3.2 Hz),4.04 (1H, dd, J=8.6, 4.6 Hz), 5.81 (1H, s, C═CHCO). MS m/z (%) of themixture: no M⁺, 411 (3), 385 (86), 355 (14), 353 (47), 325 (8), 293(30), 280 (24), 253 (65), 223 (13), 221 (20), 73 (100).

Example 10 [(aS*,4R,8R)- and[(aR*,4R,8R)-2-[4,8-bis-[(t-butyldimethylsilyl)oxy]-1-oxa-spiro[2.5]octy-6-ylidene]-ethanols(Compound 12)

To a solution of Compound 11 (190.3 mg, 0.43 mmol, a mixture of11a:11b=ca. 3:1), which was allylester compound, in dry toluene (2 mL)cooled to −78° C. was added di-iso-butylaluminum hydride (1.07 mL, 1.07mmol, 1.0 M solution in toluene), and the mixture was stirred for 1 h.The reducing agent was decomposed by adding an aqueous solution ofsaturated potassium sodium tartrate, the reaction mixture was pouredinto ice water, and then extracted with AcOEt. The organic layer wassuccessively washed with water and saturated brine, and dried overanhydrous MgSO₄, and then the solvent was distilled off. The residue waspurified by silica gel column chromatography (8 g; 10%→15%AcOEt/hexane), to yield Compound 12 (167.6 mg, 94%) as a mixture of twostereoisomers, from. 10% AcOEt-containing hexane eluate. The ratio ofthe isomers constituting the mixture was ca. 3:1. It was impossible toknow whether the major product was aS*,4R,8R isomer or aR*,4R,8R isomer.Compound 12′, which had an open-ring, was obtained from 15%AcOEt-containing hexane eluate (11 mg, 6%; obtained only for one of thestereoisomers)

12a (major product): ¹H NMR (CDCl₃) δ: 0.034 (3H, s, Si-Me), 0.056 (6H,s, Si-Me×2), 0.068 (3H, s, Si-Me), 0.87, 0.88 (each 9H, s, Si-tBu×2),1.15 (1H, t, J=5.6 Hz, OH), 2.22 (1H, dd, J=13.6, 6.9 Hz), 2.32 (1H, dd,J=13.1, 6.9 Hz), 2.39 (1H, dd, J=13.1, 3.8 Hz), 2.61 (1H, dd, J=13.6,4.1 Hz), 2.74, 2.84 (each 1H, d, J=5.4 Hz, CH₂O), 3.83-3.86 (2H, m, H-3,5), 4.13-4.20 (2H, m, CH ₂OH), 5.59 (1H, t, J=7.0 Hz, C═CHCO).

12b (minor product): ¹H NMR (CDCl₃) δ: 0.026, 0.056, 0.063, 0.09 (each3H, s, Si-Me×4), 0.86, 0.88 (each 9H, s, Si-tBu×2), 1.22 (1H, dd, J=6.5,4.7 Hz, OH), 2.16, 2.21, 2.53 (each 1H, m), 2.57 (1H, d, J=5.5 Hz,CH₂O), 2.60 (1H, m), 2.93 (1H, d, J=5.5 Hz, CH₂O), 3.71 (1H, dd, J=5.1,3.1 Hz), 4.00 (1H, dd, J=9.5, 4.6 Hz), 4.08-4.20 (2H, m, CH₂OH), 5.67(1H, t, J=6.9 Hz, C═CHCO). MS m/z (%) of the mixture: no M⁺, 357 (13),339 (100), 327 (4), 309 (14), 265 (20), 235 (26), 225 (20), 207 (38),195 (15), 177 (37), 75 (100).

12′: ¹H NMR (CDCl₃) δ: 0.07 (6H, s, Si-Me×2), 0.08, 0.10 (each 3H,Si-Me×2), 0.87, 0.91 (each 9H, s, Si-tBu×2), 1.18 (3H, s, Me), 2.19-2.38(4H, m), 2.46 (1H, d, J=13.6 Hz), 3.71 (1H, dd, J=9.6, 4.9 Hz), 3.78(1H, dd, J=4.3, 3.4 Hz), 4.09-4.16 (2H, m, CH₂OH), 5.50 (1H, t, J=7.0Hz, C═CHCO).

Example 11 [(aS*,4R,8R)- and[(aR*,4R,8R)-2-[4,8-bis-[(t-butyldimethylsilyl)oxy]-6-[2-(diphenyl-phosphinoyl)-ethylidene]-1-oxa-spiro[2.5]octane(Compound 13)

To a solution of Compound 12 (167.6 mg, 0.404 mmol, a mixture of 12a:12b=ca. 3:1), which was an allylalcohol compound, in dry THF (2 mL) cooledto 0° C. were subsequently added n-BuLi (278 μL, 0.445 mmol, 1.6 Msolution in hexane) and a solution of p-toluenesulfonyl chloride (84.7mg, 0.445 mmol) in dry THF (0.3 mL), and the mixture was stirred for 5min. In a separate vessel, a solution of diphenylphosphine (141 μL,0.810 mmol) in THF (1 mL) was prepared; and when n-BuLi (505 μL, 0.808mmol, 1.6 M solution in hexane) was added while stirring at 0° C., thesolution turned dark red. The dark red solution cooled to 0° C. wasslowly added dropwise to the above tosyl compound solution, until thereaction mixture turned red. The entire mixture was further stirred for30 min at 0° C., and water (100 μL) was added to stop the reaction. Thesolvent was evaporated from the reaction mixture, and the residue wasdissolved in CH₂Cl₂ (4 mL). To this mixture was added 10% hydrogenperoxide (6 mL). The mixture was stirred for 1 h at 0° C. To thereaction solution was added 2N sodium sulfite (Na₂SO₃), and the reactionsolution was extracted with CH₂Cl₂. The organic layer was successivelywashed with water and saturated brine, and then dried over anhydrousMgSO₄. After evaporation of the solvent, the residue was purified bysilica gel column chromatography (8 g; 30% AcOEt/hexane), to yieldCompound 13 (187.9 mg, 77%) as a mixture of two stereoisomers. The ratioof the isomers constituting the mixture was ca. 3:1. It was impossibleto know whether the major product was aS*,4R,8R isomer or aR*,4R,8Risomer.

NMR Data of the Mixture

13a (major product): ¹H NMR (CDCl₃) δ: −0.01-0.06 (12H, Si-Me×4), 0.83,0.84 (each 9H, s, Si-tBu×2), 1.83 (1H, m), 2.25-2.40 (3H, m), 2.60, 2.82(each 1H, d, J=5.5 Hz, CH₂O), 3.05-3.24 (2H, m, CH₂PO), 3.70 (1H, dd,J=5.8, 3.6 Hz), 3.83 (1H, dd, J=8.5, 4.4 Hz), 5.36 (1H, m, C═CHCO),7.44-7.77 (10H, m, arom H).

13b (minor product): ¹H NMR (CDCl₃) δ: −0.01-0.06 (12H, Si-Me×4), 0.82,0.86 (each 9H, s, Si-tBu×2), 1.93, 2.10, 2.25, 2.46 (each 1H, m, H-2,6), 2.55, 2.84 (each 1H, d, J=5.5 Hz, CH₂O), 3.05-3.24 (2H, m, CH₂PO),3.65 (1H, dd, J=5.6, 3.2 Hz), 3.89 (1H, dd, J=8.7, 4.6 Hz), 5.36 (1H, m,C═CHCO), 7.44-7.77 (10H, m, arom H). MS m/z (%) of the mixture: no M⁺,541 (100), 511 (8), 449 (39), 409 (86), 201 (26), 75 (44).

Example 121α-[(t-butyldimethylsilyl)oxy]-2β,2′-epoxy-25-[(triethylsilyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether and1α-[(t-butyldimethylsilyl)oxy]-2α,2′-epoxy-25-[(triethylsilyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 15a, b)

To a solution of Compound 13 (100.1 mg, 0.167 mmol, a mixture of 13a:13b=ca. 3:1) in dry THF (1.5 mL) cooled to −78° C. was added slowly n-BuLi(104 μL, 0.167 mmol, 1.6 M solution in hexane), to obtain dark orangesolution. After stirring for 15 min, to this colored solution was addeda solution of Compound 14a (44.0 mg, 0.114 mmol), which was aGrundmann's keton, in dry THF (0.5 mL), and the reaction mixture wasstirred for 2 h at −78° C. To the reaction solution was added saturatedNH₄Cl aqueous solution, and the reaction solution was extracted withAcOEt. The organic layer was washed with saturated brine, dried overanhydrous MgSO₄, and evaporated to remove the solvent. The residue waspurified by silica gel column chromatography (7 g; 2%→10%→40%AcOEt/hexane), to yield Compound 15 (58.4 mg, 68%) as a mixture of twostereoisomers, from 2% AcOEt-containing hexane eluate. The ratio of theisomers constituting the mixture was ca. 3:1. From the results ofExample 13, it was considered that 2β,2′-epoxy compound (15a) was themajor product. Unreacted Compound 14a (14.0 mg, 32%) and Compound 13(34.0 mg, 34%) were recovered from 10% AcOEt-containing hexane eluateand 40% AcOEt-containing hexane eluate, respectively.

NMR Data of the Mixture

15a (major product): ¹H NMR (CDCl₃) δ: 0.02 (3H, s, Si-Me), 0.055 (3H,s, Si-Me×2), 0.065 (6H, s, Si-Me), 0.55 (3H, s, H-18), 0.56 (6H, q,SiCH₂×3), 0.86, 0.88 (each 9H, s, Si-tBu×2), 0.95 (12H, t, J=7.9 Hz,SiCH₂CH ₃×3, overlapped with H-21), 1.19 (6H, s, H-26, 27), 2.27-2.38(2H, m), 2.42 (1H, dd, J=13.1, 3.6 Hz), 2.66 (1H, dd, J=13.3, 3.4 Hz),2.74, 2.82 (each 1H, d, J=5.5 Hz, CH₂O), 3.81 (1H, dd, J=7.7, 3.9 Hz),3.88 (1H, dd, J=7.0, 3.8 Hz), 5.82 (1H, d, J=11.1 Hz, H-7), 6.21 (1H, d,J=11.1 Hz, H-6).

15b (minor product): ¹H NMR (CDCl₃) δ: 0.02 (3H, s, Si-Me), 0.064 (6H,s, Si-Me×2), 0.08 (3H, Si-Me), 0.55 (3H, s, H-18), 0.56 (6H, q,SiCH₂×3), 0.86, 0.88 (each 9H, s, Si-tBu×2), 0.95 (12H, t, J=7.9 Hz,SiCH₂CH ₃×3, overlapped with H-21), 1.19 (6H, s, H-26, 27), 2.57, 2.92(each 1H, d, J=5.5 Hz, CH₂O), 3.68 (1H, m), 4.04 (1H, dd, J=9.5, 4.5 Hz,H-1), 5.82 (1H, d, J=12.1 Hz, H-7), 6.27 (1H, d, J=12.1 Hz, H-6).

Example 13 1α,25-dihydroxy-2β,2′-epoxy-19-norvitamin D₃ (CompoundYI-1a), and 1α,25-dihydroxy-2α,2′-epoxy-19-norvitamin D₃ (CompoundYI-1b), and 1α,2β,25-trihydroxy-2α-fluoromethyl-19-norvitamin D₃(Compound YI-2a), and 1α,2α,25-trihydroxy-2β-fluoromethyl-19-norvitaminD₃ (Compound YI-2b)

To a solution of Compound 15 (58.4 mg, 0.075 mmol, a mixture of15a:15b=ca. 3:1), which was a trisilylether compound, in dry THE (1 mL),was added tetrabutylammonium fluoride (301 μL, 0.301 mmol, 1.0 Msolution in THF), and stirred for 30 min at 0° C. and then for 7 h atroom temperature. To the reaction solution was added ice water, and thereaction solution was extracted with AcOEt. The organic layer was washedwith saturated brine, and dried over anhydrous MgSO₄. After removal ofthe solvent, the residue was subjected to silica gel columnchromatography (5 g; 60%→70% AcOEt/hexane), to yield a mixture (2.6 mg,8%) of Compounds YI-2a and YI-2b from the 60% AcOEt-containing hexaneeluate and a mixture (19.7 mg, 60%) of Compounds YI-1a and YI-1b fromthe 70% AcOEt-containing hexane eluate.

The mixture containing YI-1a and YI-1b was separated and purified byHPLC (LiChrosorb Si 60, 250×10 mm, hexane:CH₂Cl₂:2-propanol=50:50:8), toyield Compound YI-1a (11.0 mg) and Compound YI-1b (2.6 mg). The mixturecontaining YI-2a and YI-2b was separated and purified by HPLC (YMC-PackODS-AM SH-342-5, 150×20 mm, 20% H₂O/methanol (MeOH)), to yield CompoundYI-2a (0.9 mg) and Compound YI-2b (0.3 mg).

YI-1a (major product): ¹H NMR (CDCl₃) δ: 0.55 (3H, s, H-18), 0.94 (3H,d, J=6.4 Hz, H-21), 1.22 (6H, s, H-26, 27), 2.30 (1H, dd, J=13.5, 8.7Hz, H-10), 2.40 (1H, dd, J=13.7, 6.1 Hz, H-4), 2.60 (1H, dd, J=13.7, 3.5Hz, H-4), 2.81 (1H, m, H-9), 2.84 (1H, d, J=4.7 Hz, CH₂O), 2.96 (1H, dd,J=13.5, 4.3 Hz, H-10), 3.08 (1H, d, J=4.7 Hz, CH₂O), 3.80 (1H, m, H-3),3.99 (1H, m, H-1), 5.86 (1H, d, J=11.2 Hz, H-7), 6.39 (1H, d, J=11.2 Hz,H-6).

YI-1b (minor product): ¹H NMR (CDCl₃) δ: 0.56 (3H, s, H-18), 0.94 (3H,d, J=6.4 Hz, H-21), 1.22 (6H, s, H-26, 27), 2.30 (1H, dd, J=13.7, 6.2Hz, H-4), 2.36 (1H, dd, J=13.3, 8.6 Hz, H-10), 2.71 (1H, dd, J=13.7, 3.6Hz, H-4), 2.81 (1H, m, H-9), 2.86 (1H, dd, J=13.3, 4.3 Hz, H-10), 2.94,2.99 (each 1H, d, J=4.7 Hz, CH₂O), 3.81 (1H, m, H-3W/2≈12 Hz), 3.91 (1H,m, H-1W/2≈20 Hz), 5.87 (1H, d, J=11.2 Hz, H-7), 6.37 (1H, d, J=11.2 Hz,H-6). MS m/z (%): 432 (23, M⁺), 414 (20), 396 (23), 378 (52), 303 (12),267 (68), 135 (100).

YI-2a (major product): ¹H NMR (CDCl₃) δ: 0.53 (3H, s, H-18), 0.94 (3H,d, J=6.4 Hz, H-21), 1.22 (6H, s, H-26, 27), 2.45 (1H, dd, J=13.5, 8.9Hz, H-4), 2.49 (1H, dd, J=13.5, 54 Hz, H-4), 2.55 (1H, dd, J=14.1, 5.8Hz, H-10), 2.63 (1H, br. s, OH), 2.69 (1H, dd, J=14.1, 2.9 Hz, H-10),2.80 (1H, m, H-9), 3.86 (1H, m, H-3), 3.97 (1H, m, H-1), 4.77 (each 1H,dd, J=47.6, 9.7 Hz, CH₂F), 5.80 (1H, d, J=11.2 Hz, H-7), 6.41 (1H, d,J=11.2 Hz, H-6).

¹⁹F NMR (CDCl₃) δ: −240.6 (t, J=47.6 Hz). MS m/z (%): 452 (75, M⁺), 434(100), 414 (34), 396 (19), 378 (38), 323 (54), 305 (19), 303 (21), 287(17), 285 (18), 267 (22), 228 (24), 133 (82).

YI-2b (minor product): ¹H NMR (CDCl₃) δ: 0.55 (3H, s, H-18), 0.94 (3H,d, J=6.4 Hz, H-21), 1.22 (6H, s, H-26, 27), 2.16 (1H, dd, J=14.1, 4.0Hz, H-4), 2.27 (1H, br, t, J=≦12 Hz, H-10), 2.57 (1H, br. s, OH), 2.79(1H, m, H-9), 2.84 (1H, m, H-4), 2.88 (1H, dd, J=13.2, 4.9 Hz, H-10),3.77 (1H, m, H-1W/2≈20 Hz), 3.95 (1H, m, H-3W/2≈12 Hz), 4.69, 4.77 (each1H, dd, J=47.6, 9.6 Hz, CH₂F), 5.86 (1H, d, J=11.3 Hz, H-7), 6.29 (1H,d, J=11.2 Hz, H-6).

¹⁹F NMR (CDCl₃) δ: −240.2 (t, J=47.6 Hz). MS m/z (%): 452 (74, M⁺), 434(100), 414 (35), 396 (16), 378 (33), 323 (50), 3.5 (17), 303 (20), 287(15), 285 (16), 267 (18), 228 (24), 133 (74).

Example 141α-[(t-butyldimethylsilyl)oxy]-2β,2′-epoxy-25-[(methoxymethyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether and1α-[(t-butyldimethylsilyl)oxy]-2α,2′-epoxy-25-[(methoxymethyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 16a, b)

To a solution of Compound 13 (185.1 mg, 0.31 mmol, a mixture of 13a:13b=ca. 3:1) in dry THF (1 mL) cooled to −78° C. was added n-BuLi (193 μL,0.31 mmol, 1.6 M solution in hexane), and the resulting orange solutionwas stirred for 30 min. To this colored solution was added a solution ofCompound 14b (66:8 mg, 0.206 mmol), which was a Grundmann's keton, indry THF (1.2 mL), and the reaction mixture was stirred for 2 h at −78°C. An aqueous solution of saturated NH₄Cl was added to the reactionsolution, and then the reaction solution was extracted with AcOEt. Theorganic layer was washed with saturated brine and dried over anhydrousMgSO₄, and the solvent was evaporated. The residue was purified bysilica gel column chromatography (9 g; 3%→12%→40% AcOEt/hexane), toafford Compound 16 (96.6 mg, 67%) as a mixture of two stereoisomers,from 3% AcOEt-containing hexane eluate. The ratio of the isomersconstituting the mixture was ca. 5:1. Unreacted Compound 14b (22.0 mg,33%) and Compound 13 (43.4 mg, 23%) were recovered from 12%AcOEt-containing hexane eluate and 40% AcOEt-containing hexane eluate,respectively.

NMR Data of the Mixture

16a (major product): ¹H NMR (CDCl₃) δ: 0.02, 0.055 (each 3H, s, Si-Me),0.065 (6H, Si-Me×2), 0.55 (3H, s, H-18), 0.86, 0.87 (each 9H, s,Si-tBu×2), 0.94 (3H, d, J=6.4 Hz, H-21), 1.22 (6H, s, H-26, 27),2.28-2.37 (2H, m), 2.42 (1H, dd, J=13.1, 3.7 Hz), 2.65 (1H, dd, J=13.7,3.7 Hz), 2.74 (1H, d, J=5.5 Hz, CH₂O), 2.80 (1H, m, H-9), 2.82 (1H, d,J=5.5 Hz, CH₂O), 3.37 (3H, s, OMe), 3.81 (1H, dd, J=7.1, 3.9 Hz, H-3),3.88 (1H, dd, J=7.0, 3.9 Hz, H-1), 4.71 (2H, s, OCH₂O), 5.82 (1H, d,J=11.0 Hz, H-7), 6.21 (1H, d, J=11.0 Hz, H-6).

16b (minor product): ¹H NMR (CDCl₃) δ: 0.02-0.08 (12H, Si-Me×4), 0.55(3H, s, H-18), 0.86, 0.87 (each 9H, s, Si-tBu×2), 0.94 (3H, d, J=6.4 Hz,H-21), 1.22 (6H, s, H-26, 27), 2.57 (1H, d, J=5.5 Hz, CH₂O), 2.80 (1H,m, H-9), 2.92 (1H, d, J=5.5 Hz, CH₂O), 3.37 (3H, s, OMe), 3.68 (1H, m,H-3), 4.04 (1H, dd, J=9.1, 4.9 Hz, H-1), 4.71 (2H, s, OCH₂O), 5.82 (1H,d, J=11.2 Hz, H-7), 6.28 (1H, d, J=11.0 Hz, H-6).

Example 15 1α-hydroxy-2β,2′-epoxy-25-[(methoxymethyl)oxy]-19-norvitaminD₃ and 1α-hydroxy-2α,2′-epoxy-25-[(methoxymethyl)oxy]-19-norvitamin D₃(Compounds 17a, b)

To a solution of Compound 16 (34.4 mg, 0.049 mmol, a mixture of 16a:16bca. 5:1) in dry THF (1 mL) was added tetrabutylammonium fluoride(122.41, 0.122 mmol, 1.0 M solution in THF), and stirred for 30 min at0° C. and then for 5 h at room temperature. Ice water was added to thereaction solution, and the reaction solution was extracted with AcOEt.The organic layer was washed with saturated brine, and dried overanhydrous MgSO₄. The solvent was distilled off. The residue was purifiedby silica gel column chromatography (5 g; 50% AcOEt/hexane), to yieldCompound 17 (21.5 mg, 92%) as a mixture of two stereoisomers. The ratioof the isomers constituting the mixture was ca. 4:1.

NMR Data of the Mixture

17a (major product): ¹H NMR (CDCl₃) δ: 0.55 (3H, s, H-18), 0.93 (3H, d,J=6.4 Hz, H-21), 1.22 (6H, s, H-26, 27), 2.32 (1H, dd, J=13.5, 8.9 Hz),2.40 (1H, dd, J=13.8, 6.1 Hz), 2.62 (1H, dd, J=13.8, 3.5 Hz), 2.80 (1H,m, H-9), 2.85 (1H, d, J=4.7 Hz, CH₂O), 2.95 (1H, dd, J=13.5, 4.5 Hz),3.07 (1H, d, J=4.7 Hz, CH₂O), 3.37 (3H, s, OMe), 3.82 (1H, m), 3.98(1H), m), 4.71 (2H, s, OCH₂O), 5.86 (1H, d, J=11.1 Hz, H-7), 6.40 (1H,d, J=11.1 Hz, H-6).

17b (minor product): ¹H NMR (CDCl₃) δ: 0.55 (3H, s, H-18), 0.93 (3H, d,J=6.4 Hz, H-21), 1.22 (6H, s, H-26, 27), 2.72 (1H, m), 2.94, 2.99 (each1H, d, J=4.7 Hz, CH₂O), 3.37 (3H, s, OMe), 3.82 (1H, m), 3.91 (1H, m),4.71 (2H, s, OCH₂O), 5.86 (1H, d, J=11.1 Hz, H-7), 6.37 (1H, d, J=11.1Hz, H-6).

Example 16 1α,2β-dihydroxy-2α-methyl- and1α,2α-dihydroxy-2β-methyl-25-[(methoxymethyl)oxy]-19-norvitamin D₃(Compounds 18a, b)

To a suspension of lithium aluminum hydride (LiAlH₄, 0.5 mg, 0.014 mmol)in dry diethyl ether (0.25 mL) was added a solution of Compound 17 (6.8mg, 0.014 mmol, a mixture of 17a:17b=ca. 4:1) in dry diethyl ether (0.25mL), and the suspension was stirred for 1 h at room temperature. Apotassium sodium tartrate water was added to the reaction mixture, andthe mixture was extracted with AcOEt. The organic layer was washed withsaturated brine and dried over anhydrous MgSO₄, and the solvent wasdistilled off. The residue was purified by silica gel columnchromatography (3 g; 60% AcOEt/hexane), to afford Compound 18 (4.7 mg,69%) as a mixture of two stereoisomers. The ratio of the isomersconstituting the mixture was ca. 4:1.

NMR Data of the Mixture

18a (major product): ¹H NMR (CDCl₃) δ: 0.54 (3H, s, H-18), 0.93 (3H, d,J=6.4 Hz, H-21), 1.22 (6H, s, H-26, 27), 1.27 (3H, s, 2-Me), 2.37 (1H,dd, J=14.4, 4.6 Hz), 2.53 (1H, m), 2.79 (1H, m), 2.94 (1H, dd, J=13.6,4.3 Hz), 3.37 (3H, s, OMe), 3.74 (2H, m, H-1, 3), 4.71 (2H, s, OCH₂O),5.84 (1H, d, J=11.2 Hz, H-7), 6.30 (1H, d, J=11.2 Hz, H-6).

18b (minor product): ¹H NMR (CDCl₃) δ: 0.54 (3H, s, H-18), 0.93 (3H, d,J=6.4 Hz, H-21), 1.22 (6H, s, H-26, 27), 1.30 (3H, s, 2-Me), 2.17 (1H,m), 2.67 (1H, m), 3.37 (3H, s, OMe), 3.74 (2H, m, H-1, 3), 4.71 (2H, s,OCH₂O), 5.82 (1H, d, J=≦11 Hz, H-7), 6.34 (1H, d, J=≦11 Hz, H-6).

Example 17 1α,2β,25-trihydroxy-2α-methyl-19-norvitamin D₃ (CompoundYI-3a) and 1α,2α,25-trihydroxy-2β-methyl-19-norvitamin D₃ (CompoundYI-3b)

To a solution of Compound 18 (10.5 mg, 0.022 mmol, a mixture of 18a:18b=ca. 4:1) in dry MeOH (0.5 mL), was added camphor sulfonic acid (10.1mg, 0.044 mmol) and stirred for 30 min at 0° C. and then for 2 h at roomtemperature, and the reaction mixture was diluted with AcOEt. Theorganic layer was successively washed with 5% NaHCO₃ aqueous solutionand saturated brine, and dried over anhydrous MgSO₄. Solvents weredistilled off, and the residue was purified by silica gel columnchromatography (3 g; 70% AcOEt/hexane), to yield a mixture (8.8 mg, 93%)of Compounds YI-3a and YI-3b.

The mixture of Compounds YI-3a and YI-3b was separated and purified byHPLC (YMC-Pack ODS-AM SH-342-5, 150×20 mm, 20% H₂O/MeOH), to affordCompound YI-3a (5.2 mg) and Compound YI-3b (0.7 mg).

YI-3a: ¹H NMR (CDCl₃) δ: 0.54 (3H, s, H-18), 0.94 (3H, d, J=6.4 Hz,H-21), 1.22 (6H, s, H-26, 27), 1.27 (3H, s, 2-Me), 2.05 (1H, m, H-10),2.36 (1H, dd, J=14.4, 4.5 Hz, H-4), 2.55 (2H, m, H-4, OH), 2.79 (1H, m,H-9), 2.94 (1H, dd, J=13.5, 4.4 Hz, H-10), 3.74 (2H, m, H-1, 3), 5.84(1H, d, J=11.2 Hz, H-7), 6.30 (1H, d, J=11.2 Hz, H-6).

YI-3b: ¹H NMR (CDCl₃) δ: 0.55 (3H, s, H-18), 0.94 (3H, d, J=6.4 Hz,H-21), 1.22 (6H, s, H-26, 27), 1.30 (3H, s, 2-Me), 2.17 (1H, dd, J=13.6,8.4 Hz, H-4), 2.30 (1H, br s, OH), 2.49 (1H, dd, J=14.2, 3.3 Hz, H-10),2.62 (1H, dd, J=14.2, 6.5 Hz, H-10), 2.67 (1H, dd, J=13.6, 4.1 Hz, H-4),2.79 (1H, m, H-9), 3.73 (1H, m, H-1, W/2≈12 Hz), 3,78 (1H, m, H-3,W/2≈18 Hz), 5.82 (1H, d, J=11.2 Hz, H-7), 6.34 (1H, d, J=11.2 Hz, H-6).MS m/z (%): 434 (75, M⁺), 416 (100), 401 (16), 398 (31), 380 (21), 362(20), 3.05 (29), 287 (27), 269 (29), 251 (25), 135 (74).

Example 18 1α-[(t-butyldimethylsilyl)oxy]-2β-hydroxy-2α-ethyl- and1α-[(t-butyldimethylsilyl)oxy]-2α-hydroxy-2β-ethyl-25-[(methoxymethyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ethers (Compounds 19a, b)

To a suspension of copper (1) cyanide (CuCN, 114.6 mg, 1.280 mmol) indry Et₂O (1.5 mL) cooled to −40° C. was added a solution of methyllithium (MeLi, 2.25 mL, 2.565 mmol, 1.14 M solution in Et₂O), and themixture was stirred for 30 min. To this solution was added a solution ofCompound 16 (113.1 mg, 0.160 mmol, 16a:16b=ca. 3:1 mixture was used inthis working example) dissolved in dry Et₂O (3 mL). The reaction mixturewas stirred for 1 h at −40° C., the temperature was gradually raised to0° C., and then the mixture was further stirred for 2 h. A solution ofsaturated NH₄Cl was added to the reaction mixture to stop the reaction,and then the mixture was poured into ice water and extracted with AcOEt.The organic layer was rinsed with saturated brine, dried over anhydrousMgSO₄, and the solvent was evaporated. The residue was purified bysilica gel column chromatography (Wacogel C-300, 10 g; 2% AcOEt/hexane),to yield Compound 19 (90.3 mg, 78%) as a mixture of 2β hydroxyl productand 2α hydroxyl product, and unreacted Compound 16 (18.5 mg, 16%). Theratio of the isomers constituting Compounds 19a, b was ca. 3:1. In thisseparation step by chromatography, a fraction containing only Compound19a and a fraction containing only Compound 19b were obtained, and thesefractions were separated.

19a (major product): ¹H NMR (CDCl₃) δ: 0.06, 0.07, 0.09, 0.11 (each 3H,s, Si-Me), 0.55 (3H, s, H-18), 0.83 (9H, s, Si-tBu), 0.90 (9H, s,Si-tBu, overlapped with CH₂CH ₃), 0.93 (3H, d, J=6.5 Hz, H-21), 1.21(6H, s, H-26, 27), 1.62 (2H, m, CH ₂CH₃), 2.26 (1H, dd. J=13.6, 5.0 Hz),2.43 (2H, m), 2.52 (1H, dd, J=14.4, 4.0 Hz), 2.80 (1H, m, H-9), 3.37(3H, s, OMe), 3.78 (1H, dd, J=9.7, 5.0 Hz), 3.96 (1H, t, J=3.0 Hz), 4.71(2H, s, OCH₂O), 5.79 (1H, d, J=11.3 Hz, H-7), 6.16 (1H, d, J=11.3 Hz,H-6).

19b (minor product): ¹H NMR (CDCl₃) δ: 0.06, 0.07, 0.99, 0.11 (each 3H,s, Si-Me), 0.55 (3H, s, H-18), 0.85 (9H, s, Si-tBu), 0.91 (9H, s,Si-tBu, overlapped with CH₂CH ₃), 0.93 (3H, d, J=6.5 Hz, H-21), 1.21(6H, s, H-26, 27), 1.62 (m, CH ₂CH₃), 2.09 (1H, dd. J=13.8, 5.0 Hz),2.30 (1H, dd, J=12.8, 9.6 Hz), 2.59 (2H, m), 2.79 (1H, m, H-9),3.37 (3H,s, OMe), 3.70 (1H, dd, J=9.2, 4.4 Hz), 3.92 (1H, dd, J=4.8, 3.2 Hz),4.71 (2H, s, OCH₂O), 5.80 (1H, d, J=11.0 Hz, H-7), 6.10 (1H, d, J=11.0Hz, H-6).

Example 19 1α,2β,25-trihydroxy-2α-ethyl-19-norvitamin D₃ (CompoundYI-4a) and 1α,2α,25-trihydroxy-2β-ethyl-19-norvitamin D₃ (CompoundYI-4b)

To a solution of Compound 19b (17.8 mg, 0.025 mmol) in dry MeOH (1 mL)was added camphor sulfonic acid (48.1 mg, 0.207 mmol), and the reactionmixture was stirred for 8 h at room temperature. 5% NaHCO₃ aqueoussolution was added to the reaction mixture. The reaction mixture wasextracted with AcOEt, and the organic layer was washed with saturatedbrine, and dried over anhydrous MgSO₄. The solvent was evaporated. Theresidue was purified by silica gel column chromatography (3 g; 50%AcOEt/hexane), to yield Compound YI-4b (11.0 mg, 99%).

The major product 19a (6.2 mg, 0.009 mmol) was reacted and after-treatedin the same manner as described above, to give Compound YI-4a (2.3 mg,60%).

YI-4a (major product): ¹H NMR (CDCl₃) δ: 0.54 (3H, s, H-18), 0.94 (3H,d, J=6.4 Hz, H-21), 0.98 (3H, t, J=7.5 Hz, CH₂CH ₃), 1.22 (6H, s, H-26,27), 1.68, 1.85 (each 1H, m, CH ₂CH₃), 2.26 (1H, dd, J=13.5, 9.2 Hz),2.38 (1H, dd, J=13.8, 6.4 Hz), 2.47 (1H, dd, J=13.8, 3.5 Hz), 2.80 (2H,m, H-9, 10), 3.83 (2H, m, H-1, 3), 5.84 (1H, d, J=11.0 Hz, H-7), 6.33(1H, d, J=11.0 Hz, H-6). UV λmax (EtOH): 244, 252, 261 nm.

YI-4b (minor product): ¹H NMR (CDCl₃) δ: 0.55 (3H, s, H-18), 0.94 (3H,d, J=6.4 Hz, H-21), 0.99 (3H, t, J=7.5 Hz, CH₂CH ₃), 1.22 (6H, s, H-26,27), 1.72, 1.81 (each 1H, m, CH ₂CH₃), 2.18 (1H, dd, J=13.8, 6.5 Hz,H-4), 2.44 (1H, dd, J=13.5, 8.5 Hz, H-10), 2.63 (1H, dd, J=13.5, 4.2 Hz,H-10), 2.72 (1H, dd, J=13.8, 3.3 Hz, H-4), 2.79 (1H, m, H-9 (, 3.73 (1H,m, W/2-17 Hz, H-1), 3.88 (1H, m, W/2-13 Hz, H-3), 5.84 (1H, d, J=11.2Hz, H-7), 6.31 (1H, d, J=11.2 Hz, H-6).

Example 20 1α,2β,25-trihydroxy-2α-methoxymethyl-19-norvitamin D₃(Compound YI-5a) and 1α,2α,25-trihydroxy-2β-methoxymethyl-19-norvitaminD₃ (Compound YI-5b)

To a solution of Compound 16 (49.7 mg, 0.070 mmol, a mixture of16a:16b=ca. 5:1) in dry MeOH (1 mL), was added camphor sulfonic acid(98.2 mg, 0.423 mmol), and the reaction mixture was stirred for 1 h at0° C. and then for 4 h at room temperature.

To the reaction mixture, 5% NaHCO₃ aqueous solution was added. The wholemixture was extracted with AcOEt, and the organic layer was washed withsaturated brine, dried over anhydrous MgSO₄, and the solvent wasdistilled off The residue was purified by silica gel columnchromatography (5 g; 70% AcOEt/hexane), to give a mixture (28.5 mg, 87%)of Compounds YI-5a and YI-5b. The mixture of YI-5a and YI-5b wasseparated and purified by HPLC (YMC-Pack ODS-AM SH-342-5, 150×20 mm, 15%H₂O/MeOH), to obtain Compound YI-5a (8.2 mg) and Compound YI-5b (1.6mg).

YI-5a: ¹H NMR (CDCl₃) δ: 0.53 (3H, s, H-18), 0.93 (3H, d, J=6.4 Hz,H-21), 1.22 (6H, s, H-26, 27), 2.41 (2H, m, H-4), 2.53 (1H, dd, J=14.1,5.7 Hz, H-10), 2.68 (2H, m, H-10, OH), 2.79 (1H, m, H-9), 2.97 (1H, brs, OH), 3.43 (3H, s, OMe), 3.69, 3.73 (each 1H, d, J=9.5 Hz, OCH₂O),3.88 (2H, m, H-1, 3), 5.81 (1H, d, J=11.2 Hz, H-7), 6.39 (1H, d, J=11.2Hz, H-6).

YI-5b (minor product): ¹H NMR (CDCl₃) δ: 0.55 (3H, s, H-18), 0.94 (3H,d, J=6.4 Hz, H-21), 1.22 (6H, s, H-26, 27), 2.13 (1H, dd, J=13.8, 3.6Hz, H-4), 2.21 (1H, br t, J=≦12 Hz, H-10), 2.77-2.89 (4H, m, H-4, 9, 10,OH), 3.43 (3H, s, OMe), 3.65, 3.77 (each 1H, d, J=9.4 Hz, OCH₂O), 3.80(1H, m, H-1), 3.85 (1H, m, H-3), 5.88 (1H, d, J=11.2 Hz, H-7), 6.27 (1H,d, J=11.2 Hz, H-6). MS m/z (%): 464 (52, M⁺), 446 (74), 428 (23), 410(10), 401 (65), 383 (100), 335 (13), 317 (10), 299 (12), 281 (13), 222(12).

Example 21 (20S)-1α-[(t-butyldimethylsilyl)oxy]-2β,2′-epoxy- and(20S)-1α-[(t-butyldimethylsilyl)oxy]-2α,2′-epoxy-25-[(triethylsilyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ethers (Compounds 20a, b)

To a solution of Compound 13 (351.0 mg, 0.586 mmol, 13a:13b=ca. 2:1mixture was used in this working example) in dry THF (3 mL) cooled to−78° C. was slowly added n-BuLi (371 μL, 0.586 mmol, 1.58 M solution inhexane), and a dark orange solution was obtained. After stirring for 15min, to this colored solution was added a solution of Compound 14c(154.2 mg, 0.391 mmol), which was a Grundmann's keton, in dry THF (2.3mL), and the whole mixture was stirred for 2 h at −78° C. A solution ofsaturated NH₄Cl was added to the reaction solution, and the reactionsolution was extracted with AcOEt. The organic layer was rinsed withsaturated brine, and dried over anhydrous MgSO₄. The solvent wasdistilled off. The residue was purified by silica gel columnchromatography (15 g; 2%→10%→60% AcOEt/hexane), to yield Compound 20(227.0 mg, 75%) as a mixture of two stereoisomers, from 2%AcOEt-containing hexane eluate. The ratio of the isomers constitutingthe mixture was ca. 3:1. Unreacted Compound 14c (35.8 mg) and Compound13 (99.0 mg) were recovered from 10% AcOEt-containing hexane eluate and60% AcOEt-containing hexane eluate, respectively.

NMR Data of the Mixture

20a (major product): ¹H NMR (CDCl₃) δ: 0.02 (3H, s, Si-Me), 0.05 (3H, s,Si-Me×2), 0.06 (6H, s, Si-Me), 0.55 (3H, s, H-18), 0.56 (6H, q,SiCH₂×3), 0.86, 0.88 (each 9H, s, Si-Btu×2, overlapped with H-21), 0.95(9H, t, J=7.9 Hz, SiCH₂CH ₃×3), 1.19 (6H, s, H-26, 27), 2.42 (1H, dd,J=13.2, 3.6 Hz), 2.68 (1H, dd, J=13.5, 3.8 Hz), 2.79, 2.82 (each 1H, d,J=5.5 Hz, CH₂O), 3.81 (1H, dd, J=7.2, 3.9 Hz, H-3), 3.87 (1H, dd, J=7.0,3.9 Hz, H-1), 5.82 (1H, d, J=11.1 Hz, H-7), 6.21 (1H, d, J=11.1 Hz,H-6).

20b (minor product): ¹H NMR (CDCl₃) δ: 0.02-0.07 (12H, Si-Me×4), 0.55(3H, s, H-18), 0.56 (9H, m, SiCH₂×3, overlapped with H-18), 0.86, 0.88(each 9H, s, Si-tBu×2, overlapped with H-21), 0:95 (9H, t, J=7.9 Hz,SiCH₂CH ₃×3), 1.19 (6H, s, H-26, 27), 2.57, 2.92 (each 1H, d, J=5.5 Hz,CH₂O), 3.69 (1H, m, H-3), 4.03 (1H, d, J=9.3, 4.7 Hz, H-1), 5.82 (1H, d,J=0.7 Hz, H-7), 6.28 (1H, d, J=10.7 Hz, H-6).

Example 22 (20S)-1α,25-dihydroxy-2β,2′-epoxy- and(20S)-1α,25-dihydroxy-2α,2′-epoxy-19-norvitamin D₃ (20-Epi-YI-1a, 1b),and (20S)-1α,2β,25-trihydroxy-2α-fluoromethyl-19-norvitamin D₃ (Compound20-Epi-YI-2a), and(20S)-1α,2α,25-trihydroxy-2β-fluoromethyl-19-norvitamin D₃ (Compound20-Epi-YI-2b)

To a solution of Compound 20 (50.0 mg, 0.0645 mmol, a mixture of20a:20b=ca. 3:1), which was a tolylsilylether compound, in dry THF (1mL), was added tetrabutylammonium fluoride (387 μL, 0.387 mmol, 1.0 Msolution in THF), and the reaction solution was stirred for 7 h at roomtemperature. Ice water was added to the reaction solution, and thereaction solution was extracted with AcOEt. The organic layer was washedwith saturated brine and dried over anhydrous MgSO₄, and the solvent wasdistilled off. The residue was purified by silica gel columnchromatography (5 g; 50%→70% AcOEt/hexane), to yield a mixture ofCompounds 20-Epi-YI-2a and 20-Epi-YI-2b (3.5 mg, 12%;20-Epi-YI-2a:20-Epi-YI-2b=ca.4:1) from 50% AcOEt-containing hexaneeluate, and a mixture of Compounds 20-Epi-YI-1a and 20-Epi-YI-1b (23.0mg, 82%; 20-Epi-YI-1a:20-Epi-YI-1b=ca.3:1) from 70% AcOEt-containinghexane eluate.

The mixture of Compounds 20-Epi-YI-2a and 20-Epi-YI-2b was separated andpurified by HPLC (YMC-Pack ODS-AM SH-342-5, 150×20 mm, 20% H₂O/MeOH), togive Compound 20-Epi-YI-2a (2.1 mg) and Compound 20-Epi-YI-2b (0.5 mg),respectively.

The mixture of Compounds 20-Epi-YI-1a and 1b was separated and purifiedby HPLC (LiChrosorb Si 60, Hibar, 250×4 mm, hexane:CH₂Cl₂:MeOH=50:50:8),to afford Compound YI-20-Epi-1a (15.8 mg) and Compound YI-20-Epi-1b (6.1mg; Z-isomer), respectively.

YI-20-Epi-1a: ¹H NMR (CDCl₃) δ: 0.55 (3H, s, H-18), 0.86 (3H, d, J=6.5Hz, H-21), 1.22 (6H, s, H-26, 27), 2.30 (1H, dd, J=13.4, 8.8 Hz, H-10),2.40 (1H, dd, J=13.7, 6.1 Hz, H-4), 2.61 (H, dd, J=13.7, 3.5 Hz, H-4),2.80 (1H, m, H-90, 2.84 (1H, d, J=4.7 Hz, CH₂O), 2.95 (1H, dd, J=13.4,4.3 Hz, H-10), 3.08 (1H, d, J=4.7 Hz, CH₂O), 3.81 (1H, m, H-3), 3.98(1H, m, H-1), 5.86 (1H, d, J=11.2 Hz, H-7), 6.39 (1H, d, J=11.2 Hz,H-6). MS m/z (%): 432 (M⁺, 29), 414 (29), 396 (18), 378 (56), 303 (18),267 (48), 138 (100).

YI-20-Epi-1b: ¹H NMR (CDCl₃) δ: 0.56 (3H, s, H-18), 0.86 (3H, d, J=6.5Hz, H-21), 1.22 (6H, s, H-26, 27), 2.30 (1H, dd, J=13.7, 6.2 Hz, H-4),2.36 (1H, dd, J=13.5, 8.7 Hz, H-10), 2.72 (1H, dd, J=13.7, 3.7 Hz, H-4),2.81 (1H, m, H-9β), 2.86 (1H, dd, J=13.5, 4.4 Hz, H-10), 2.94, 2.99(each 1H, d, J=4.7 Hz, CH₂O), 3.82 (1H, m, H-3), 3.90 (1H, m, H-1), 5.88(1H, d, J=11.2 Hz, H-7), 6.38 (1H, d, J=11.2 Hz, H-6). MS m/z (%): 432(M⁺, 68), 414 (77), 396 (35), 378 (50), 303 (35), 267 (42), 133 (100).

20-Epi-YI-2a (major product): ¹H NMR (CDCl₃) δ: 0.53 (3H, s, H-18), 0.85(3H, d, J=6.5 Hz, H-21), 1.21 (6H, s, H-26, 27), 2.45 (1H, dd, J=13.3,8.7 Hz, H-4), 2.49 (1H, dd, J=13.3, 5.5 Hz, H-4), 2.56 (1H, dd, J=14.2,5.8 Hz, H-10), 2.62 (1H, d, J=1.5 Hz, OH), 2.69 (1H, dd, J=14.2, 2.9 Hz,H-10), 2.79 (1H, m, H-9), 3.87 (1H, m, H-3), 3.97 (1H, m, H-1), 4.71,4.76 (each 1H, dd, J=47.8, 9.7 Hz, CH₂F), 5.81 (1H, d, J=11.2 Hz, H-7),6.40 (1H, d, J=11.2 Hz, H-6). ¹⁹F NMR (CDCl₃) δ: −240.3 (t, J=47.8 Hz).

20-Epi-YI-2b (minor product): ¹H NMR (CDCl₃) δ: 0.55 (3H, s, H-18), 0.86(3H, d, J=6.5 Hz, H-21), 1.22 (6H, s, H-26, 27), 2.17 (1H, dd, J=14.0,4.0 Hz, H-4), 2.27 (1H, br. t, J=≦11 Hz, H-10), 2.57 (1H, d, J=1.8 Hz,OH), 2.79 (1H, m, H-9), 2.84 (1H, m, H-4), 2.89 (1H, dd, J=13.2, 5.0 Hz,H-10), 3.76 (1H, m, H-1), 3.95 (1H, m, H-3), 4.70, 4.76 (each 1H, dd,J=47.6, 9.5 Hz, CH₂F), 5.86 (1H, d, J=11.2 Hz, H-7), 6.29 (1H, d, J=11.2Hz, H-6). ¹⁹F NMR (CDCl₃) δ: −240.2 (t, J=47.6 Hz).

Example 23 (20S)-1α,2β,25-trihydroxy-2α-methyl-19-norvitamin D₃(Compound 20-Epi-YI-3a), and(20S)-1α,2α,25-trihydroxy-2β-methyl-19-norvitamin D₃ (Compound20-Epi-YI-3b)

To a solution of Compounds 20-Epi-YI-1a and 20-Epi-YI-1b (23.0 mg, 0.053mmol, 20-Epi-YI-1a: 20-Epi-YI-1b=ca. 3:1), which were epoxy compounds,in dry THF (0.25 mL) was added LiAlH₄ (2 mg, 0.053 mmol), and themixture was stirred for 7 h at room temperature. After 2 h and 6 h fromthe reaction, additional LiAlH₄ (2 mg) was added, respectively.Potassium sodium tartrate water was added to the reaction mixture, andthe mixture was extracted with AcOEt. The organic layer was washed withsaturated brine, and dried over anhydrous MgSO₄. The solvent wasdistilled off. The residue was purified by silica gel columnchromatography (3 g; 60% AcOEt/hexane), to give a mixture of Compounds20-Epi-YI-3a and 20-Epi-YI-3b (15.5 mg, 67%; the ratio was unknown).

The mixture of 20-Epi-YI-3a and 20-Epi-YI-3b was separated and purifiedby HPLC (YMC-Pack ODS-AM SH-342-5, 150×20 mm, 20% H₂O/MeOH), to giveCompound 20-Epi-YI-3a (6.3 mg). It was impossible to isolate Compound20-Epi-YI-3b as a pure compound.

20-Epi-YI-3a (major product): ¹H NMR (CDCl₃) δ: 0.54 (3H, s, H-18), 0.86(3H, d, J=6.5 Hz, H-21), 1.22 (6H, s, H-26, 27), 1.27 (3H, s, 2-Me),2.07 (1H, m, H-10), 2.36 (1H, dd, J=14.4, 4.6 Hz, H-4), 2.54.(2H, m,H-4, OH), 2.79 (1H, m, H-9), 2.94 (1H, dd, J=13.5, 4.4 Hz), 3.74 (2H, m,H-1, 3), 5.85 (1H, d, J=11.3 Hz, H-7), 6.30 (1H, d, J=11.3 Hz, H-6).

Example 24 (20S)-1α-[(t-butyldimethylsilyl)oxy]-2β-hydroxy-2α-ethyl- and(20S)-1α-[(t-butyldimethylsilyl)oxy]-2α-hydroxy-2β-ethyl-25-[(triethylsilyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ethers (Compounds 21a, b)

To a suspension of CuCN (101.9 mg, 1.138 mmol) in dry Et₂O (1 mL) cooledto −40° C. was gradually added MeLi (2.0 mL, 2.272 mmol, 1.14 M solutionin hexane), and the mixture was stirred for 30 min at −40° C. To thissolution was added slowly a solution of Compound 20 (110.3 mg, 0.142mmol, a mixture of ca. 3:1 was used in this working example), which wasan epoxy compound, in dry Et₂O (1.5 mL), and the reaction mixture wasstirred for 1 h at −40° C., the temperature was gradually raised to 0°C., and then the mixture was further stirred for 2 h. Saturated NH₄Claqueous solution was added to the reaction mixture, and the reactionmixture was extracted with AcOEt. The organic layer was rinsed withsaturated brine, and dried over anhydrous MgSO₄. The solvent wasdistilled off, and the residue was purified by silica gel columnchromatography (10 g; 2% AcOEt/hexane), to afford Compound 21 (98.5 mg,88%) as a mixture of two stereoisomers. The ratio of the isomersconstituting the mixture was 21a:21b=ca. 3:1.

21: ¹H NMR (CDCl₃) δ: 0.06, 0.07, 0.09, 0.10 (each 3H, s, Si-Me×4), 0.54(3H, s, H-18), 0.56 (6H, q, J=7.9 Hz, Si—CH₂×3), 0.84, 0.91 (each 9H, s,Si-tBu×2, overlapped with H-21), 0.94 (9H, t, J=7.9 Hz, Si—CH₂CH₃×3,overlapped with CH₂CH ₃), 1.19 (6H, s, H-26, 27), 2.80 (1H, m, H-9),3.78, 3.92 (ca. 3:1) (1H, m, H-3), 3.70, 3.95 (ca. 1:3) (1H, m, H-1),5.79 (1H, d, J=11.3 Hz, H-7), 6.10, 6.16 (ca. 1:3) (1H, d, J=11.3 Hz,H-6).

Example 25 (20S)-1α,2β,25-trihydroxy-2α-ethyl-19-norvitamin D₃ (Compound20-epi-YI-4a), and (20S)-1α,2α,25-trihydroxy-2β-ethyl-19-norvitamin D₃(Compound 20-epi-YI-4b

To a solution of Compound 21 (98.5 mg, 0.124 mmol, a mixtureof21a:21b=ca. 3:1) in dry MeOH (2 mL), was added camphor sulfonic acid(173.5 mg, 0.747 mmol), and the mixture was stirred for 6 h at roomtemperature. To the reaction mixture, 5% NaHCO₃ aqueous solution wasadded, and the solution was extracted with AcOEt. The organic layer waswashed with saturated brine, dried over anhydrous MgSO₄, and the solventwas distilled off. The residue was purified by silica gel columnchromatography (6 g; 50% AcOEt/hexane), to obtain a mixture (45.0 mg,81%) containing Compounds 20-epi-YI-4a and 20-epi-YI-4b in a ratio ofca. 3:1.

The mixture containing Compounds 20-epi-YI-4a and 20-epi-YI-4b in aratio of ca. 3:1 was separated and purified by HPLC (YMC-Pack ODS-AMSH-342-5, 20% H₂O/MeOH, 8 ml/min), to yield Compound 20-epi-YI-4a (27.4mg) and Compound 20-epi-YI-4b (7.3 mg), respectively.

20-epi-YI-4a: ¹H NMR (CDCl₃) δ: 0.53 (3H, s, H-18), 0.85 (3H, d, J=6.5Hz, H-21), 0.98 (3H, t, J=7.5 Hz, CH₂CH ₃), 1.21 (6H, s, H-26, 27), 2.25(1H, dd, J=13.7, 8.9 Hz, H-10), 2.37 (1H, dd, J=14.0, 6.2 Hz, H-4), 2.45(2H, m, H-4, OH), 2.80 (2H, m, H-{tilde over (9)}₁), 3.85 (2H, m, H-1,3), 5.83 (1H, d, J=11.2 Hz, H-7), 6.31 (1H, d, J=11.2 Hz H-6). UV λmax(EtOH): 244, 252, 261 nm.

20-epi-YI-4b: ¹H NMR (CDCl₃) δ: 0.55 (3H, s, H-18), 0.85 (3H, d, J=6.5Hz, H-21), 0.99 (3H, t, J=7.5 Hz, CH₂CH ₃), 1.22 (6H, s, H-26, 27), 2.18(1H, dd, J=13.8, 6.6 Hz, H-4), 2.45 (1H, dd, J=13.6, 8.5 Hz, H-10), 2.62(1H, dd, J=13.6, 4.3 Hz, H-10), 2.71 (1H, dd, J=13.8, 3.4 Hz, H-4), 2.80(1H, m, H-9), 3.74 (1H, dd, J=8.5, 4.3 Hz, H-1), 3.88 (1H, dd, J=6.6,3.4 Hz, H-3), 5.84 (1H, d, J=11.2 Hz, H-7), 6.31 (1H, d, J=11.2 Hz,H-6). UV λmax (EtOH): 244, 252, 261 nm.

Example 26 (20S)-1α,2β,25-trihydroxy-2α-methoxymethyl-19-norvitamin D₃(Compound 20-epi-YI-5a), and(20S)-1α,2α,25-trihydroxy-2β-methoxymethyl-19-norvitamin D₃ (Compound20-epi-YI-5b)

To a solution of Compound 20 (10.4 mg, 0.013 mmol, a mixture of20a:20b=ca. 3:1) in dry MeOH (0.5 mL), was added camphor sulfonic acid(18.7 mg, 0.080 mmol), and the mixture was stirred for 1 h at 0° C. andthen for 4 h at room temperature. 5% NaHCO₃ aqueous solution was addedto the reaction mixture, and the mixture was extracted with AcOEt. Theorganic layer was washed with saturated brine, and dried over anhydrousMgSO₄. The solvent was distilled off. The residue was purified by silicagel column chromatography (5 g; 70% AcOEt/hexane), to give a mixture(5.0 mg, 81%) containing Compounds 20-epi-YI-5a and 20-epi-YI-5b in aratio of ca. 3:1. The mixture containing 20-epi-YI-5a and 20-epi-YI-5bin a ratio of ca. 3:1 was separated and purified by HPLC (YMC-PackODS-AM SH-342-5, 150×20 mm, 15% H₂O/MeOH); to yield Compounds20-epi-YI-5a (2.0 mg) and 20-epi-YI-5b (0.8 mg), respectively.

20-epi-YI-5a: ¹H NMR (CDCl₃) δ: 0.53 (3H, s, H-18), 0.85 (3H, d, J=6.5Hz, H-21), 1.21 (6H, s, H-26, 27), 2.41 (2H, m, H-4, OH), 2.53 (1H, dd,J=14.1, 5.6 Hz, H-10), 2.68 (2H, m, H-10, OH), 2.80 (1H, m, H-9), 2.94(1H, s, OH), 3.44 (3H, s, OMe), 3.69, 3.74 (each 1H, d, J=9.5 Hz,OCH₂O), 3.89 (2H, m, H-1, 3), 5.82 (1H, d, J=11.2 Hz, H-7), 6.39 (1H, d,J=11.2 Hz, H-6). UV λmax (EtOH): 244, 252, 261 nm.

20-epi-YI-5b: ¹H NMR (CDCl₃) δ: 0.55 (3H, s, H-18), 0.85 (3H, d, J=6.4Hz, H-21), 1.21 (6H, s, H-26, 27), 2.12 (1H, dd, J=13.9, 3.4 Hz, H-4),2.21 (1H, br. t, J=≦12 Hz, H-10), 2.77-2.89 (4H, m, H-4, 9, 10), 2.89(1H, s, OH), 3.43 (3H, s, OMe), 3.65, 3.77 (each 1H, d, J=9.5 Hz,OCH₂O), 3.79 (1H, m, H-1), 3.84 (1H, m, H-3), 5.88 (1H, d, J=11.2 Hz,H-7), 6.27 (1H, d, J=11.2 Hz, H-6). UV λmax (EtOH): 244, 252, 261 nm.

Example 27(20S)-1α-[(t-butyldimethylsilyl)oxy]-2α-[(trimethylsilyl)oxy]- and(20S)-1α-[(t-butyldimethylsilyl)oxy]-2β-[(trimethylsilyl)oxy]-25-[(triethylsilyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ethers (Compounds 23a, 23b)

To solution of Compound 22 (435.2 mg, 0.660 mmol, a mixture of22a:22b=ca. 2:1) in dry THF (5 mL) cooled to −78° C. was added n-BuLi(412 μL, 0.660 mmol, 1.6 M solution in hexane), and the resultingsolution was stirred for 15 min. To this solution was added a solutionof Compound 14c (173.8 mg, 0.440 mmol), which was a Grundmann's keton,in dry THF (3 mL), and the mixture was stirred for 2 h at −78° C.Saturated NH₄Cl aqueous solution was added to the reaction solution, andthe solution was extracted with AcOEt. The organic layer was rinsed withsaturated brine, dried over anhydrous MgSO₄, and the solvent wasdistilled off. The residue was purified by silica gel columnchromatography (20 g; 2% AcOEt/hexane), to give Compound 23 (243.4 mg,66%) as a mixture of two stereoisomers. The ratio of the isomers 23a and23b constituting the mixture was ca. 3:2. Unreacted Compound 14c (30.0mg, 17%) and Compound 22 (157.6 mg) were recovered from 5% AcOEt/hexaneeluate and 5% AcOEt/hexane eluate, respectively.

NMR Data of the Mixture

23a (major product): ¹H NMR (CDCl₃) δ: 0.04, 0.055, 0.058, 0.063 (each3H, s, Si-Me×4), 0.12 (9H, Si-Me×3), 0.54 (3H, s, H-18), 0.56 (6H, q,J=7.9 Hz, SiCH₂×3), 0.85 (3H, d, J=6.5 Hz, H-21), 0.87, 0.88 (each 9H,s, Si-tBu×2), 0.94 (9H, t, J=7.9 Hz, SiCH₂ CH ₃×3), 1.19 (6H, s, H-26,27), 2.30 (1H, m), 2.50 (2H, m), 2.79 (1H, m, H-9), 3.54 (1H, m, H-2),3.80 (1H, m, H-3), 3.88 (1H, m, H-1), 5.81 (1H, d, J=11.1 Hz, H-7), 6.10(1H, d, J=11.1 Hz, H-6).

23b (minor product): ¹H NMR (CDCl₃) δ: 0.04, 0.06 (each 3H, s, Si-Me×2),0.07 (6H, s, Si-Me×2), 0.12 (9H, Si-Me×3), 0.53 (3H, s, H-18), 0.56 (6H,q, J=7.8 Hz, SiCH₂×3), 0.84 (3H, d, J=6.6 Hz, H-21), 0.86, 0.89 (each9H, s, Si-tBu×2), 0.94 (9H, t, J=7.8 Hz, SiCH₂ CH ₃×3), 1.19 (6H, s,H-26, 27), 2.10 (1H, m), 2.44 (2H, m), 2.79 (1H, m, H-9), 3.6 (1H, m,H-2), 3.80 (1H, dd, J=8.7, 4.5 Hz, H-1), 3.94 (1H, m, H-3), 5.79 (1H, d,J=11.2 Hz, H-7), 6.13 (1H, d, J=11.2 Hz, H-6).

Example 28 (20S)-1α-(t-butyldimethylsilyloxy)-2α,25 -dihydroxy- and(20S)-1α-(t-butyldimethylsilyloxy)-2β,25 -dihydroxy-19-norvitamin D₃t-butyldimethylsilyl ethers (Compounds 24a, 24b)

Compound 23 (182.5 mg, 0.218 mmol, a mixture of 23a:23b=ca. 3:2) wasdissolved in a mixture of THF, AcOH, and water (9.5 mL, 8:8: 1, v/v/v),and the resulting solution was stirred for 2 h at 0° C. and then for 2.5h at room temperature. The reaction solution was diluted with AcOE, andthen was successively washed with 5% NaHCO₃ aqueous solution andsaturated brine. The organic layer was dried over anhydrous Na₂SO₄. Thesolvent was distilled off, and the residue was purified by silica gelcolumn chromatography (10 g; 2% AcOEt/hexane), to give Compound 24a(39.1 mg, 28%) and Compound 24b (26.0 mg, 18%). The total yield was 46%.

24a: ¹H NMR (CDCl₃) δ: 0.067, 0.077, 0.083, 0.10 (each 3H, s, Si-Me×4),0.54 (3H, s, H-18), 0.86 (3H, d, J=6.6 Hz, H-21), 0.87, 0.88 (each 9H,s, Si-tBu×2), 1.22 (6H, s, H-26, 27), 2.27 (1H, d, J=3.2 Hz, OH), 2.31(1H, dd, J=12.6, 3.7 Hz), 2.48 (2H, m), 2.79 (1H, m, H-9), 3.51 (1H, m,H-2), 3.91, (1H, m, H-3), 4.00 (1H, m, H-1), 5.80 (1H, d, J=11.1 Hz,H-7), 6.15 (1H, d, J=11.1 Hz, H-6).

24b: ¹H NMR (CDCl₃) δ: 0.06, 0.07, 0.08, 0.10 (each 3H, s, Si-Me×4),0.53 (3H, s, H-18), 0.86, 0.90 (each 9H, s, Si-tBu×2, overlapped withH-21), 1.21 (6H, s, H-26, 27), 2.18 (1H), dd, J=13.0, 4.5 Hz), 2.39 (3H,m), 2.80 (1H, m, H-9), 3.59 (1H, m, H-2), 4.00 (2H, m, H-1, 3), 5.80(1H, d, J=11.2 Hz, H-7), 6.18 (1H, d, J=11.2 Hz, H-6).

Example 29(20S)-1α-[(t-butyldimethylsilyl)oxy]-2α-{2-[(t-butyldimethylsilyl)oxy]-ethoxy}-25-hydroxy-19-norvitaminD₃ t-butyldimethylsilyl ether (Compound 25a)

To a mixed solution of Compound 24a (17.0 mg, 0.026 mmol) in dry DMF anddry THF (9:1, 1 mL, v/v) cooled to 0° C., were added NaH (31.4 mg, 0.786mmol, 60% paraffin liquid) and (2-bromoethoxy)-tert-butyldimethylsilane(27 μL, 0.126 mmol), and the mixture was vigorously stirred. After 22 h,ice water was added to the reaction solution, and then the solution wasextracted with a mixed solution of AcOEt and hexane (1:1, v/v). Theorganic layer was washed with saturated brine, and dried over anhydrousMgSO₄. Following evaporation of the solvent, the residue was purified bysilica gel column chromatography (5 g; 7% AcOEt/hexane), to affordCompound 25a (15.4 mg, 73%), and Compound 24a (2.8 mg, 16%), which wasthe unreacted starting material, was recovered from 20% AcOEt/hexaneeluate.

25a: ¹H NMR (CDCl₃) δ: 0.04-0.08 (18H, Si-Me×6), 0.54 (3H, s, H-18),0.87, 0.89, 0.91 (each 9H, s, Si-tBu×3 overlapped with H-21), 1.21 (6H,s, H-26, 27), 2.79 (1H, m, H-9), 3.21 (1H, m, H-2), 3.7-3.9 (4H, m,OCH₂CH₂O), 3.96 (1H, m, H-3), 4.14 (1H, m, H-1), 5.81 (1H, d, J=11.2 Hz,H-7), 6.15 (1H, d, J=11.2 Hz, H-6).

Example 30(20S)-1α-[(t-butyldimethylsilyl)oxy]-2β-{2-[(t-butyldimethylsilyl)oxy]-ethoxy}-25-hydroxy-19-norvitaminD₃ t-butyldimethylsilyl ether (Compound 25b)

To Compound 24b (15.3 mg, 0.024 mmol) in dry DMF (1 mL) cooled to 0° C.,were added NaH (18.9 mg, 0.471 mmol, 60% paraffin liquid) and(2-bromoethoxy)-tert-butyldimethylsilane (20 μL, 0.093 mmol), and themixture was vigorously stirred. After 22 h, ice water was added to thereaction solution, and then the solution was extracted with a mixedsolution of AcOEt and hexane (1:1, v/v). The organic layer was washedwith saturated brine and dried over anhydrous MgSO₄, and the solvent wasdistilled off. The residue was purified by silica gel columnchromatography (5 g; 7% AcOEt/hexane), to afford Compound 25b (12.0 mg,63%), and Compound 24b (3.4 mg, 22%), which was the unreacted startingmaterial, was recovered from 20% AcOEt/hexane eluate.

25b: ¹H NMR (CDCl₃) δ: 0.05-0.07 (18H, Si-Me×6), 0.53 (3H, s, H-18),0.86, 0.88, 0.89 (each 9H, s, Si-tBu×3, overlapped with H-21), 1.21 (6H,s, H-26, 27), 2.13 (1H, dd, J=12.8, 4.0 Hz, H-10), 2.35 (2H, m, H-4),2.46 (1H, m, H-10), 2.80 (1H, m, H-9), 3.28 (1H, m, H-2), 3.61 (1H, m),3.73 (2H, m), 3.83 (1H, m), 3.96 (1H, dd, J=8.8, 4.3 Hz, H-1), 4.04 (1H,m, H-3), 5.79 (1H, d, J=11.1 Hz, H-7), 6.14 (1H, d, J=11.1 Hz, H-6).

Example 31 (20S)-1α,25-dihydroxy-2α-(2-hydroxy-ethoxy)-19-norvitamin D₃(Compound 20-epi-YI-6a)

To a solution of Compound 25a (15.4 mg, 0.019 mmol) in dry MeOH (0.5mL), was added camphor sulfonic acid (26.6 mg, 0.114 mmol), and thereaction mixture was stirred for 2 h at room temperature. 5% NaHCO₃aqueous solution was added to the reaction mixture, and the mixture wasextracted with AcOEt. The organic layer was washed with saturated brine,dried over anhydrous MgSO₄, and the solvent was distilled off. Theresidue was purified by silica gel column chromatography (3 g; 2%MeOH/AcOEt), and further purified by HPLC (YMC-Pack ODS-AM SH-342-5,150×20 mm, 20% H₂O/MeOH, 8 mL/min), to yield Compound 20-epi-YI-6a(6.4-mg, 72%).

20-Epi-YI-6a: ¹H NMR (CDCl₃) δ: 0.55 (3H, s, H-18), 0.85 (3H, d, J=6.5Hz, H-21 (6H, s, H-26, 27), 2.19 (2H, m, H-4, 10), 2.33, 2.41, 2.56(each 1H, br. s, OH×3), 2.63 (1H, dd, J=13.2, 4.3 Hz, H-4), 2.80 (1H, m,H-9), 2.84 (1H, dd, J=14.4, 5.4 Hz, H-10), 3.37 (1H, dd, J=7.8, 2.8 Hz,H-2), 3.72-3.83 (4H, m, OCH₂CH₂O), 3.96 (1H, m, H-3), 4.14 (1H, m, H-1),5.83 (1H, d, J=11.2 Hz, H-7), 6.34 (1H, d, J=1.2 Hz, H-6). UV λmax(EtOH): 243, 252, 261 nm.

Example 32 (20S)-1α,25-dihydroxy-2β-(2-hydroxy-ethoxy)-19-norvitamin D₃(Compound 20-epi-YI-6b)

To a solution of Compound 25b (12.0 mg, 0.015 mmol) in dry MeOH (0.5mL), was added camphor sulfonic acid (20.7 mg, 0.089 mmol), and thereaction mixture was stirred for 2 h at room temperature. 5% NaHCO₃aqueous solution was added to the reaction mixture. The mixture wasextracted with AcOEt. The organic layer was washed with saturated brine,and dried over anhydrous MgSO₄. The solvent was distilled off. Theresidue was purified by silica gel column chromatography (3 g; 2%MeOH/AcOEt), and further purified by HPLC (YMC-Pack ODS-AM SH-342-5,150×20 mm, 20% H₂O/MeOH, 8 mL/min), to yield Compound 20-epi-YI-6b (5.6mg, 81%).

20-epi-YI-6b: ¹H NMR (CDCl₃) δ: 0.54 (3H, s, H-18), 0.85 (3H, d, J=6.5Hz, H-21), 1.21 (6H, s, H-26, 27), 2.35 (1H, br. d, J=14.2 Hz, H-4),2.48 (1H, dm, J=14.2 Hz, H-4), 2.79 (1H, m, H-9), 3.09 (1H, dd, J=13.5,3.7 Hz, H-10), 3.29 (1H, dd, J=8.7, 2.7 Hz, H-2), 3.67 (1H, m),3.76-3.89 (4H, m, H-1, OCH₂CH₂O), 4.17 (1H, m, H-3), 5.84 (1H, d, J=11.2Hz, H-7), 6.28 (1H, d, J=11.2 Hz, H-6). UV λmax (EtOH): 243, 252, 261nm.

Example 33(20S)-1α-[(t-butyldimethylsilyl)oxy]-2-oxo-25-hydroxy-19-norvitamin D₃t-butyldimethylsilyl ether (Compound 26)

To a solution of oxalyl chloride (18 μL, 0.206 mmol) in dry CH₂Cl₂ (1mL) cooled to −78° C. was added a solution of DMSO (29 μL, 0.414 mmol)in dry CH₂Cl₂ (0.2 mL), and the solution was stirred for 5 min. To thecooled stirred solution, a solution of Compound 24 (61.0 mg, 0.094 mmol,a mixture of isomers 24a:24b=ca. 3:2) in dry CH₂Cl₂ (1.2 mL) was added.The reaction mixture was stirred for 15 min at −78° C., and Et₃N (131μL, 0.940 mmol) was added. The mixture was stirred for 30 min at −78° C.and then for 10 min at 0° C., followed by addition of ice water. Thesolution was extracted with CH₂Cl₂. The organic layer was washed withsaturated brine, dried over anhydrous MgSO₄, and the solvent wasdistilled off. The residue was purified by silica gel columnchromatography (5 g; 20% AcOEt/hexane), to afford Compound 26 (52.0 mg,86%) as a single compound.

26: ¹H NMR (CDCl₃) δ: 0.055, 0.065, 0.069, 0.10 (each 3H, s, Si-Me×4),0.55 (3H, s, H-18), 0.87, 0.89 (each 9H, s, Si-tBu×2, overlapped withH-21), 1.22 (6H, s, H-26, 27), 2.45 (1H, dd, J=13.5, 8.7 Hz), 2.52 (1H,dd, J=14.2, 4.1 Hz), 2.66 (1H, dd, J=13.5, 5.5 Hz), 2,72 (1H, dd,J=14.2, 6.3 Hz), 2.83 (1H, m, H-9), 4.35 (1H, dd, J=6.3, 4.1 Hz), 4.55(1H, dd, J=8.7, 5.5 Hz), 5.81 (1H, d, J=11.2 Hz, H-7), 6.35 (1H, d,J=11.2 Hz, H-6).

Example 34 E-isomer and Z-isomer of(20S)-1α-[(t-butyldimethylsilyl)oxy]-2-cyanomethylene-25-hydroxy-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 27a, 27b)

To a solution of diethyl cyanomethyl phosphonate (24 μL, 0.148 mmol) indry THF (1 mL) cooled to −40° C., was added n-BuLi (95 μL, 0.151 mmol,1.58 M solution in hexane), and the mixture was stirred for 15 min. Tothe mixture, a solution of Compound 26 (48.7 mg, 0.075 mmol) in dry THF(1.2 mL) was gradually added. Stirring was continued for 1.5 h at −40°C., then saturated NH₄Cl aqueous solution was added to the reactionmixture, and the mixture was extracted with AcOEt. The organic layer waswashed with saturated brine, and dried over anhydrous MgSO₄. The solventwas distilled off. The residue was purified by silica gel columnchromatography (5 g; 10% AcOEt/hexane), to afford Compound 27 (50.0 mg,99%) as a mixture of two stereoisomers. The ratio of Isomer 27a(E-isomer) and Isomer 27b (Z-isomer) constituting the mixture was ca.1:1.

27a: ¹H NMR (CDCl₃) δ: 0.054, 0.067, 0.099, 0.121 (each 3H, s, Si-Me×4),0.55 (3H, s, H-18), 0.83, 0.92 (each 9H, s, Si-tBu×2), 0.86 (3H, d,J=6.5 Hz, H-21), 1.22 (6H, s, H-26, 27), 2.80 (1H, m, H-9), 3.12 (1H, m,H-10), 4.46 (1H, m, H-1), 4.99 (1H, t, J=2.8 Hz, H-3), 5.47 (1H, d,J=1.8 Hz, C═CHCN), 5.82 (1H, d, J=11.1 Hz, H-7), 6.19 (1H, d, J=11.1 Hz,H-6).

27b: ¹H NMR (CDCl₃) δ: 0.063, 0.075, 0.112, 0.132 (each 3H, s, Si-Me×4),0.54 (3H, s, H-18), 0.83, 0.92 (each 9H, s, Si-tBu×2), 0.86 (3H, d,J=6.5 Hz, H-21), 1.22 (6H, s, H-26, 27), 2.80 (1H, m, H-9), 2.99 (1H, m,H-10), 4.57 (1H, m, H-3), 5.04 (1H, t, J=2.8 Hz, H-1), 5.47 (1H, d,J=1.8 Hz, C═CHCN), 5.79, (1H, d, J=11.1 Hz, H-7), 6.32 (1H, d, J=11.2Hz, H-6, 7).

Example 35 E-isomer and Z-isomer of(20S)-1α-[(t-butyldimethylsilyl)oxy]-2-[2-(hydroxy)-ethylidene]-25-hydroxy-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 29a, 29b)

To a solution of Compound 27 (20.0 mg, 0.030 mmol, a mixture of27a:27b=ca. 1:1) in dry toluene (1 mL) cooled to −78° C. was addeddiisobutylaluminum hydride (60 μL, 0.060 mmol, 1.0 M solution inhexane). After 3 h, the reaction temperature was raised to −20° C. Afterstirring for 1 h, additional diusobutylaluminum hydride (30 AL, 0.030mmol, 1.0 M solution in hexane) was added, and stirring was furthercontinued for 5.5 h. The reducing agent was decomposed by adding anaqueous solution of saturated potassium sodium tartrate, thereafter thereaction mixture was poured into ice water, and extracted with AcOEt.The organic layer was washed with saturated brine, dried over anhydrousMgSO₄, and the solvent was distilled off. The residue was dissolved inEtOH (1 mL), and NaBH₄ (1.1 mg, 0.030 mmol) was added. The mixture wasstirred for 1 h at 0° C. Ice water was added to the reaction solution,and the solution was extracted with AcOEt. The organic extract waswashed with saturated brine, and dried over anhydrous MgSO₄. Solvent wasremoved by evaporation, and the residue was purified by silica gelcolumn chromatography (4 g; 15% AcOEt/hexane), to give Compound 29a (5.5mg) and Compound 29b (5.0 mg). The total yield was 52%. The unreactedstarting material, Compound 27, was recovered (7.5 mg, 38%).

29a: ¹H NMR (CDCl₃) δ: 0.02, 0.07, 0.08 (3H, 3H, 6H, s, Si-Me×4), 0.55(3H, s, H-18), 0.85, 0.92 (each 9H, s, Si-tBu×2, overlapped with H-21),1.22 (6H, s, H-26, 27), 2.29 (2H, m, H-4), 2.79 (1H, m, H-9), 2.88 (1H,dd, J=12.7, 4.3 Hz, H-10), 4.19 (1H, dd, J=12.7, 6.8 Hz, CH₂OH), 4.31(1H, dd, J=12.7, 6.7 Hz, CH₂OH), 4.37 (1H, dd, J=9.7, 4.3 Hz, H-1), 4.81(1H, t, J=3.8 Hz, H-3), 5.72 (1H, t, J=6.8 Hz, C═CH), 5.85 (1H, d,J=11.2 Hz, H-7), 6.15 (1H, d, J=11.2 Hz, H-6).

29b: ¹H NMR (CDCl₃) δ: 0.01, 0.07, 0.08, 0.09 (each 3H, s, Si-Me×4),0.54 (3H, s, H-18), 0.83, 0.93 (each 9H, s, Si-tBu×2), 0.85 (3H, d,J=6.5 Hz, H-21), 1.22 (6H, s, H-26, 27), 2.14 (1H, br. t, J=≦11.5 Hz,H-4),2.55 (1H, dd, J=12.3, 5.0 Hz, H-4),2.82 (2H, m, H-9, 10), 4.22 (1H,dd, J=12.3, 7.1 Hz, CH₂OH), 4.30 (each 1H, dd, J=12.7, 7.0 Hz, CH₂OH),4.47 (1H, m, H-3), 4.86 (1H, t, J=3.1 Hz, H-1), 5.72 (1H, m, C═CH), 5.81(1H, d, J=11.1 Hz, H-7), 6.25 (1H, d, J=11.1 Hz, H-6).

Example 36 (20S)-1α,25-dihydroxy-2-[2-(hydroxy)-ethylidene-19-norvitaminD₃ (E-isomer) (Compound 20-epi-YI-8a)

To a solution of Compound 29a (11.0 mg, 0.016 mmol) in dry MeOH (0.5mL),was added camphor sulfonic acid (11.4 mg, 0.049 mmol) and thereaction mixture was stirred for 2 h at room temperature. 5% NaHCO₃aqueous solution was added to the reaction mixture, and the mixture wasextracted with AcOEt. The organic layer was washed with saturated brine,dried over anhydrous MgSO₄, and the solvent was distilled off. Theresidue was purified by silica gel column chromatography (3 g; 3%MeOHI/AcOEt), to afford Compound 20-epi-YI-8a (6.4 mg, 88%).

20-epi-YI-8a: ¹H NMR (CDCl₃) δ: 0.54 (3H, s, H-18), 0.86 (3H, d, J=6.5Hz, H-21), 1.21 (6H, s, H-26, 27), 2.42 (2H, m, H-4), 2.81 (1H, m, H-9),3.15 (1H, d, J=12.8, 4.9 Hz, H-10), 4.15 (1H, dd, J=12.4, 5.9 Hz, CH₂OH), 4.39 (2H, m, H-1, CH₂ OH), 4.84 (1H, m, H-3), 5.80 (1H, m, C═CH),5.88 (1H, d, J=11.1 Hz, H-7), 6.29 (1H, d, J=11.1 Hz, H-6). UV λmax(EtOH): 246, 254, 263 nm.

Example 37(20S)-1α,25-dihydroxy-2-[2-(hydroxyl)-ethylidene]-19-norvitamin D₃(Z-isomer) (Compound 20-Epi-YI-8b)

A mixture of Compound 29b (11.0 mg, 0.016 mmol) and camphor sulfonicacid (11.4 mg, 0.049 mmol) in dry MeOH (0.5 mL) was stirred for 2 h atroom temperature. A 5% NaHCO₃ aqueous solution was added, and themixture was extracted with AcOEt. The organic phase was washed withsaturated brine, and dried over anhydrous MgSO₄. Evaporation of thesolvent in vacuo left the residue, which was purified by silica gelcolumn chromatography (3 g; 3% MeOH/AcOEt) to afford Compound20-Epi-YI-8b (4.8 mg, 66%).

20-Epi-YI-8b: ¹H NMR (CDCl₃) δ: 0.55 (3H, s, H-18), 0.85 (3H, d, J=6.5Hz, H-21), 1.21 (6H, s, H-26, 27), 2.21 (1H, br. t. J=≦13 Hz, H-4), 2.33(1H, dm, H-10), 2.70 (1H, d, J=12.8, 4.7 Hz, H-4), 2.82 (2H, m, H-9,10),4.24 (1H, dd, J=12.6, 6.4 Hz, CH₂OH), 4.38 (1H, dd, J=12.6, 7.4 Hz,CH₂OH), 4.46 (1H, m, H-3), 4.87 (1H, t, J=4.2 Hz, H-1), 5.83 (2H, m,H-7, C═CH), 6.40 (1H, d, J=11.1 Hz, H-6). UV λmax (EtOH): 246, 254, 263nm.

Example 38 (aS*,2R,6R)-and(aR*,2R,6R)-{[4-benzyloxy-2,6-bis-[(t-butyldimethylsilyl)oxy]-cyclohexylidene}-acetonitrile(Compound 30)

To a solution of diethyl(cyanomethyl)phosphonate (112 μL, 0.69 mmol) indry THF (1 mL) cooled to −78° C. was added n-BuLi (493 μL, 0.69 mmol,1.4 M solution in hexane). The mixture was stirred for 15 min, and asolution of 6 (160 mg, 0.345 mmol) prepared in Example 4 in dry THF (1.2mL) was added slowly. Stirring was continued for 1.5 h at 0° C. afterwhich time the reaction mixture was quenched with a saturated NH₄Claqueous solution, and extracted with AcOEt. The AcOEt layer was washedwith saturated brine, and dried over anhydrous MgSO₄. Solvent wasevaporated in vacuo, and the residue was purified by silica gel columnchromatography (5 g; 2% AcOEt/hexane) to afford Compound 30 (162 mg,96%) as a mixture of two stereoisomers. The ratio of the stereoisomersconstituting the mixture was ca. 1:2. It was impossible to know whetherthe major product was aS*,2R,6R isomer or aR*,2R,6R isomer.

NMR Data of the Mixture

30a (minor product, less polar isomer): ¹H NMR (CDCl₃) δ: 0.05, 0.06,0.08, 0.11 (each 3H, Si-Me×4), 0.85, 0.91 (each 9H, s, Si-tBu×2),1.32-1.48 (2H, m), 2.28 (1H, m), 2.39 (1H, m), 3.96 (1H, m, H-1), 4.54(2H, s, PhCH ₂), 4.56 (1H, m), 4.98 (1H, m), 5.41 (1H, d, J=2.0 Hz,C═CH), 7.25-7.35 (5H, m, arom. H).

30b (major product, more polar isomer): ¹H NMR (CDCl₃) δ: 0.07, 0.08,0.09, 0.11 (each 3H, Si-Me×4), 0.84, 0.91 (each 9H, s, Si-tBu×2),1.60-1.73 (2H, m), 2.22 (2H, m), 3.85 (1H, m, H-1), 4.57, 4.61 (each 1H,d, J=12.1 Hz, PhCH ₂), 4.94-5.00 (2H, m, H-3, 5), 5.43 (1H, d, J=1.5 Hz,C═CH), 7.25-7.33 (5H, m, arom. H). MS m/z (%) of the mixture: no M⁺, 403(47), 91 (100).

Example 39 (aS*,2R,6R)-and(aR*,2R,6R)-{[4-benzyloxy-2,6-bis-[(t-butyldimethylsilyl)oxy]-cyclohexylidene}-acetaldehyde(Compound 31)

To a solution of Compound 30 (310 mg, 0.635 mmol, 30a:30b=ca. 1:2) indry toluene (3 mL) cooled to −78° C. was slowly added diisobutylaluminumhydride (763 μL, 0.763 mmol, 1.0 M solution in toluene), and the mixturewas stirred for 1.5 h. Excess reagent was decomposed by adding anaqueous solution of saturated potassium sodium tartrate, therebyquenching reaction, and into the mixture was poured ice water, and thenextracted with AcOEt. The organic layer was washed with saturated brine,dried over anhydrous MgSO₄, and evaporated in vacuo. The residue waspurified by silica gel column chromatography (13 g; 5% AcOEt/hexane) toafford Compound 31 (288.5 mg, 93%) as a mixture of two stereoisomers.The ratio of the stereoisomers constituting the mixture was ca. 1:2. Itwas impossible to know whether the major product was aS*,2R,6R isomer oraR*,2R,6R isomer.

NMR Data of the Mixture

31a (minor product, less polar isomer): ¹H NMR (CDCl₃) δ: 0.03-0.07 (12IEt Si-Me×4), 0.85, 0.92 (each 9H, s, Si-tBu×2), 1.47 (2H, m), 2.33,2.44 (each 1H, m), 3.97 (1H, m, H-1), 4.56 (2H, s, PhCH ₂), 4.69 (1H,ddd, J=11.8, 5.3, 1.7 Hz), 5.53 (1H, m), 6.16 (1H, dd, J=7.9, 1.6 Hz,C═CH), 7.26-7.36 (5H, m, arom. H), 10.09 (1H, d, J=7.8 Hz, CHO).

31b (major product, more polar isomer): ¹H NMR (CDCl₃) δ: 0.03-0.07(12H, Si-Me×4), 0.88 (18H, s, Si-tBu×2), 1.78, 1.90, 2.04, 2.17 (each1H, m), 3.93 (1H, m, H-1), 4.53, 4.58 (each 1H, d, J=11.8 Hz, PhCH ₂),4.61 (1H, m), 5.12 (1H, dd, J=8.9, 4.3 Hz), 5.88 (1H, d, J=7.7 Hz,C═CH), 7.25-7.36 (5H, m, arom. H), 10.49 (1H, d, J=7.7 Hz, CHO). MS m/z(%) of the mixture: no M⁺, 449 (32), 433 (3), 358 (4), 341 (13), 325(7), 317 (5), 209 (10), 91 (100).

Example 40 (aS*,2R,6R)-and(aR*,2R,6R)-{[4-benzyloxy-2,6-bis-[(t-butyldimethylsilyl)oxy]-cyclohexylidene}-ethanol(Compound 32)

To a solution of Compound 31 (288 mg, 0.587 mmol, 31a:31b=ca. 1:2) inEtOH (1 mL) cooled to 0° C. was added NaBH₄ (26.6 mg, 0.704 mmol).After, the reaction mixture was stirred for 1 h at 0° C., into thereaction mixture was poured ice water, and extracted with AcOEt. Theorganic layer was washed with saturated brine, and dried over anhydrousMgSO₄. Solvents were removed in vacuo, and the residue was purified bysilica gel column chromatography (10 g; 15% AcOEt/hexane) to yieldCompound 32 (283.3 mg, 98%) as a mixture of two stereoisomers. The ratioof the stereoisomers constituting the mixture was ca. 2:1. It wasimpossible to know whether the major product was aS*,2R,6R isomer oraR*,2R,6R isomer.

NMR Data of the Mixture

32a (major product, less polar isomer): ¹H NMR (CDCl₃) δ: 0.008, 0.04,0.10, 0.11 (each 3H, s, Si-Me×4), 0.85, 0.92 (each 9H, s, Si-tBu×2),1.55 (1H, m), 1.68 (1H, q, J=10.8 Hz), 2.08 (1H, m), 2.20 (1H, m), 2.94(1H, dd, J=10.0, 4.3 Hz, H-1), 3.90 (1H, tt, J=10.0, 4.3 Hz, H-1), 4.02(1H, ddd, J=13.5, 9.2, 7.0 Hz, CH ₂OH), 4.34 (1H, m, H-3, 5), 4.40 (1H,m, CH ₂OH), 4.54 (2H, s, PhCH ₂), 4.69 (1H, dd, J=10.8, 4.0 Hz, H-3, 5),5.62 (1H, t, J=5.8 Hz, C═CH), 7.24-7.35 (5H, m, arom. H).

32b (minor product, more polar isomer): ¹H NMR (CDCl₃) δ: −0.01, 0.05(each 3H, s, Si-Me×2), 0.07 (6H, s, Si-Me×2), 0.83, 0.92 (each 9H, s,Si-tBu×2), 1.30-1.41 (2H, m), 2.21 (1H, m), 2.38 (1H, m), 3.94 (1H, tt,J=11.3, 4.3 Hz, H-1), 4.23 (2H, m, CH ₂OH), 4.48 (1H, m, H-3, 5), 4.53,4.57 (each H, d, J=11.8 Hz, PhCH ₂), 4.86 (1H, m, H-3, 5), 5.70 (1H, dt,J=7.1, 1.8 Hz, C═CH), 7.24-7.35 (5H, m, arom. H). MS m/z (%) of themixture: no M⁺, 474 (8), 435 (3), 360 (1), 327 (25), 303 (8), 91 (100).

Example 41 (aS*,3R,5R)-and (aR*,3R,5R)-{3,5-bis-[(t-butyldimethylsilyl)oxy]-4-[2-(t-butyldimethylsilyl)oxy]-ethylidene}-cyclohexyloxymethyl}-benzene(Compound 33)

A mixture of Compound 32 (55 mg, 0.112 mmol, 32a:32b=ca. 2:1), imidazole(18.3 mg, 0.269 mmol), and tert-butyldimethylsilyl chloride (20.2 mg,0.134 mmol) in dry DMF (1 mL) cooled to 0° C. was stirred for 1.5 h.Into the reaction mixture was poured ice water, and extracted withAcOEt-hexane (v/v. 1:1). The organic phase was washed with saturatedbrine, and dried over anhydrous MgSO₄. Solvents were removed in vacuo,and the residue was purified by silica gel column chromatography (5 g,2% AcOEt/hexane) to yield Compound 33 (62 mg, 91%) as a mixture of twostereoisomers. The ratio of the stereoisomers constituting the mixturewas ca. 2:1. It was impossible to know whether the major product wasaS*,2R,6R isomer or aR*,2R,6R isomer.

NMR Data of the Mixture

33a (major product, less polar isomer): ¹H NMR (CDCl₃) δ: 0.02, 0.04,0.051, 0.06 (each 3H, s, Si-Me×4), 0.048 (6H, s, Si-Me×2), 0.86, 0.88,0.91 (each 9H, s, Si-tBu×3), 1.57-1.68 (2H, m), 2.02 (1H, m), 2.10 (1H,m), 3.86 (1H, m, H-1), 4.36 (1H, m), 4.38 (1H, m, CH ₂OTBS), 4.52, 4.55(each 1H, d, J=11.9 Hz, PhCH ₂), 4.63 (1H, m), 4.65 (1H, m, CH ₂OTBS),5.35 (1H, m, C═CH), 7.24-7.35 (5H, m, arom. H).

33b (minor product, more polar isomer): ¹H NMR (CDCl₃) δ: −0.01, 0.04,0.053, 0.054 (each 3H, s, Si-Me×4), 0.06 (6H, s, Si-Me×2), 0.83, 0.88,0.92 (each 9H, s, Si-tBu×3), 1.30-1.40 (2H, m), 2.19 (1H, m), 2.36 (1H,m), 3.93 (1H, tt, J=6.9, 4.3 Hz, H-1), 4.24 (2H, m, CH ₂OTBS), 4.45 (1H,m, H-3 or 5), 4.53, 4.56 (each 1H, d, J=11.8 Hz, PhCH ₂), 4.83 (1H, m),5.60 (1H, td, J=6.5, 1.8 Hz, C═CH), 7.24-7.35 (5H, m, arom. H). MS m/z(%) of the mixture: no M⁺, 591 (1), 549 (23), 474 (8), 441 (27), 417(29), 285 (13), 91 (100).

Example 423,5-bis-[(t-butyldimethylsilyl)oxy]-4-{[2-(t-butyldimethylsilyl)oxy]-ethyl}-cyclohexanone(Compound 35)

A mixture of Compound 33 (116.5 mg, 0.192 mmol, 33a:33b=ca. 2:1) andpalladium, 10 wt % on carbon (11.7 mg) in EtOH (5 mL) was hydrogenatedunder an atmospheric pressure of H₂ at room temperature. After vigorousstirring for 21 h, the reaction mixture was filtered through a pad ofCelite. The pad was washed with AcOEt, and the combined filtrate wasevaporated in vacuo. The residue was purified by silica gel columnchromatography (15 g; 5% AcOEt/hexane) to afford Compound 34 (42.7 mg,43%).

To a solution of oxalyl chloride (9 μL, 0.099 mmol) in dry CH₂Cl₂ (0.3mL) cooled to −78° C. was added a solution of DMSO (14 μL, 0.197 mmol)in dry CH₂Cl₂ (0.3 mL). After being stirred for 5 min, a solution ofCompound 34 (42.7 mg, 0.082 mmol) in dry CH₂Cl₂ (0.5 mL) was added. Thereaction mixture was stirred for 15 min, and Et₃N (57 μL, 0.358 mmol)was added. The mixture was stirred for 30 min at −78° C. and for 1 h atroom temperature, after which time it was quenched with ice water, andextracted with CH₂Cl₂. The CH₂Cl₂ extract was washed with saturatedbrine, and dried over anhydrous MgSO₄. The solvent was evaporated togive the residue, which was purified by silica gel column chromatography(4 g, 2% AcOEt/hexane) to afford Compound 35 (38.0 mg, 89% based oncoumpound 34) as a single compound.

35: ¹H NMR (CDCl₃) δ: 0.04-0.06 (18H, Si-Me×6), 0.86, 0.87, 0.90 (each9H, s, Si-tBu×3), 1.69, 1.78 (each 1H, m, CH ₂CH₂OTBS), 1.96 (1H, ddd,J=13.1, 6.9, 3.1 Hz, H-4), 2.30 (1H, dd, J=14.5, 6.9 Hz), 2.45 (2H, m),2.62 (1H, dd, J=14.5, 4.0 Hz), 3.67-3.80 (2H, m, CH ₂OTBS), 4.14, 4.38(each 1H, m, H-3, 5). MS m/z (%): no M⁺, 459 (31), 327 (41), 195 (100).

Example 43 (aS*,3R,5R)-and(aR*,3R,5R)-{3,5-bis-[(t-butyldimethylsilyl)oxy]-4-{[2-(t-butyldimethylsilyl)oxy]-ethyl}-cyclohexylidene}-methylacetate (Compound 36)

To a solution of diisopropylamine (90 μL, 0.641 mmol) in dry THF (1 mL)cooled to −78° C. was added n-BuLi (458 μL, 0.641 mmol, 1.4 M solutionin hexane). After stirring for 15 min, to the solution was added methyl(trimethylsilyl)acetate (105 μL, 0.641 mmol). After stirring for 10 min,to this solution was added slowly a solution of Compound 35 (165.7 mg,0.321 mmol) dissolved in dry THF (1.3 mL), and stirring was continuedfor 2 h at −78° C. The mixture was quenched with a saturated NH₄Claqueous solution, and extracted with AcOEt. The organic phase was washedwith saturated brine, dried over anhydrous MgSO₄, and evaporated invacuo. The residue was purified by silica gel column chromatography (6g; 2% AcOEt/hexane) to give Compound 36 (163.0 mg, 89%) as a mixture oftwo stereoisomers. The ratio of the stereoisomers constituting themixture was ca. 1:1.

36 (mixture of isomers): ¹H NMR (CDCl₃) δ: 0.03-0.08 (18H, s, Si-Me×6),0.84-0.89 (27H, s, Si-tBu×3), 1.58-1.77 (3H, m, H-4, CH₂ CH₂OTBS), 2.14(1H, m), 2.26 (1H, m), 2.47 (1H, dd, J=13.4, 3.8 Hz), 2.62, 2.70 (1:1)(1H, m), 3.22 (1H, m), 3.62-3.73 (2H, m, CH₂ OTBS), 3.668, 3.674 (1:1)(3H, s, COOMe), 3.90, 4.16 (each 1H, H-3, 5), 5.65, 5.69 (1:1) (1H, s,C═CH). MS m/z (%): no M⁺, 557 (2), 515 (49). 483 (5), 425 (3), 383 (52),351 (22), 309 (33), 277 (23), 251 (20), 177 (82), 73 (100).

Example 44 (aS*,3R,5R)-and(aR*,3R,5R)-{3,5-bis-[(t-butyldimethylsilyl)oxy]-4-[2-(t-butyldimethylsilyl)oxy]-ethyl]-cyclohexylidene}-ethanol(Compound 37)

To a solution of Compound 36 (163.0 mg, 0.284 mmol, 36a:36b=ca. 1:1) indry toluene (1.5 mL) cooled to −78° C. was added diisobutylaluminumhydride (853 μL, 0.853 mmol, 1.0 M solution in toluene), and the mixturewas stirred for 1 h. Excess of reagents were decomposed by adding anaqueous solution of saturated potassium sodium tartrate. The mixture waspoured into ice water, and extracted with AcOEt. The organic layer wassuccessively washed with water and saturated brine, and dried overanhydrous MgSO₄. Evaporation of the solvent in vacuo gave the residue,which was purified by silica gel column chromatography (6 g; 5%AcOEt/hexane) to afford Compound 37 (143.0 mg, 92%) as a mixture of twostereoisomers in ca. 1:1 ratio.

37 (mixture of isomers): ¹H NMR (CDCl₃) δ: 0.03-0.06 (18H, s, Si-Me×6),0.86-0.89 (27H, s, Si-tBu×3), 1.6-1.8 (3H, m, H-4, CH₂ CH₂OTBS),2.00-2.24 (4H, m, H-2, 6), 3.60-3.74 (2H, m, CH₂ OTBS), 3.78-3.91 (1H,m), 4.02-4.18 (3H, m, CH₂ OH), 5.47, 5.51 (1:1) (1H, t, J=7.1 Hz, C═CH).MS m/z (%): no M⁺, 487 (3), 469 (9), 459 (9), 394 (11), 355 (17), 337(19), 263 (57), 211 (74), 171 (86), 131 (100), 73 (100).

Example 45 (aS*,3R,5R)-and(aR*,3R,5R)-{3,5-bis-[(t-butyldimethylsilyl)oxy]-4-[2-(t-butyldimethylsilyl)oxy]-ethyl]-cyclohexylidene}ethyldiphenylphosphineoxide (Compound 38)

To a solution of Compound 37 (97.8 mg, 0.179 mmol, 37a:37b ca. 1:1) indry THF (1 mL) cooled to 0° C. was added n-BuLi (141 μL, 0.197 mmol, 1.4M solution in hexane), a solution of p-toluenesulfonyl chloride (37.6mg, 0.197 mmol) in dry THF (0.3 mL) was added in this order, and themixture was stirred for 5 min. To this solution of the tosylate wasadded slowly a red solution freshly prepared from diphenylphosphine (62μL, 0.358 mmol) in THF (0.5 mL) and n-BuLi (255 μL, 0.358 mmol, 1.4 Msolution in hexane) at 0° C. until the orange color persisted. Theentire mixture was stirred for 30 min at 0° C., and quenched by addingwater (50 μL). The solvent was evaporated in vacuo, and the crudeproduct was dissolved in CH₂Cl₂ (3 mL). To this mixture was added 10%hydrogen peroxide (4.5 mL). The mixture was stirred for 1 h at 0° C.,and CH₂Cl₂ phase was separated. The organic layer was successivelywashed with cold 2N Na₂SO₃, water and saturated brine, and dried overanhydrous MgSO₄. After evaporation of the solvent, the residue waspurified by silica gel column chromatography (6 g; 50% AcOEt/hexane) toafford Compound 38 (110.5 mg, 84%) as a mixture of two stereoisomers ina ratio of ca. 1:1.

38 (mixture of isomers): ¹H NMR (CDCl₃) δ: −0.01-0.02 (18H, s, Si-Me×6),0.82-0.86 (27H, s, Si-tBu×3), 3.00-3.20 (2H, m, CH₂ PO), 3.56-3.75, 3.99(3H, m, CH₂ OTBS, H-3 or 5), 3.77, 3.99 (ca. 1:1) (1H, m, H-3 or 5),5.24 (1H, m, C═CH), 7.43-7.75 (10H, m, arom. H). MS m/z (%): no M⁺, 671(100), 539 (63), 464 (15), 407 (21), 202 (53).

Example 46(20S)-1α-[(t-butyldimethylsilyl)oxy]-2α-{[2-(t-butyldimethylsilyl)oxy]-ethyl}-and(20S)-1α-[(t-butyldimethylsilyl)oxy]-2β-{[2-(t-butyldimethylsilyl)oxy]-ethyl}-25-[(triethylsilyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 39a, 39b)

To a solution of Compound 38 (100.3 mg, 0.138 mmol, 38a:38b ca. 1:1) indry THF (1 mL) cooled to −78° C. was added slowly n-BuLi (87 μL, 0.138mmol, 1.58 M solution in hexane), and the resulting dark orange solutionwas stirred for 15 min. To this colored solution was added a solution ofGrundmann's ketone 14c (36.2 mg, 0.092 mmol) in dry THF (1.2 mL), andthe reaction mixture was stirred for 2 h at −78° C., quenched with asaturated NH₄Cl aqueous solution, and extracted with AcOEt. The AcOEtlayer was washed with saturated brine, dried over anhydrous MgSO₄, andevaporated in vacuo. The residue was purified by silica gel columnchromatography (10 g; 2% AcOEt/hexane) to afford Compound 39 (53.5 mg,64%) as a mixture of 39a (2α-isomer):39b (2β-isomer) =ca. 1:2 ratio. Theunreacted starting material 14c (10.3 mg, 28%) and Compound 38 (23.4 mg)were recovered.

39: ¹H NMR (CDCl₃) δ: 0.03-0.07 (18H, s, Si-Me×6), 0.54 (3H, s, H-18),0.56 (6H, q, J=7.9 Hz, SiCH₂×3), 0.84-0.90 (30H, Si-tBu×3, overlappedwith H-21), 0.94 (9H, t, J=7.9 Hz, SiCH₂ CH₃ ×3), 1.19 (6H, s, H-26,27), 2.45, 2.58 (ca. 1:2) (1H, m, H-4), 2.79 (1H, m, H-9), 3.60-3.73(2H, m, CH₂ CH₂ O), 3.79, 4.09 (each 1H, m, H-1, 3), 5.81 (1H, m, H-7),6.12 (1H, m, H-6).

Example 47 (20S)-1α,25-dihydroxy-2α-(2-(hydroxyethyl)-and(20S)-1α,25-dihydroxy-2β-(2-(hydroxyethyl)-19-norvitamin D₃ (Compounds20-Epi-YI-7a and 20-Epi-YI-7b)

A mixture of Compound 39 (53.5 mg, 0.059 mmol, 39a:39b=ca. 1:2) andcamphor sulfonic acid (109.8 mg, 0.437 mmol) in dry MeOH (1 mL) wasstirred for 2 h at room temperature. A 5% NaHCO₃ aqueous solution wasadded, and the solution was extracted with AcOEt. The organic phase waswashed with saturated brine, and dried over anhydrous MgSO₄. Afterevaporation of the solvent in vacuo, the residue was purified by silicagel column chromatography (5 g; 3% MeOH/AcOEt) to afford Compounds20-Epi-YI-7a and 7b (21.2 mg, 80%).

The mixture of Compounds 20-Epi-YI-7a and 7b was separated by HPLC(YMC-Pack ODS-AM SH-342-5, 20% H₂O/MeOH to give Compounds 20-Epi-YI-7a(6.3 mg) and 20-Epi-YI-7b (11.5 mg), respectively.

20-Epi-YI-7a: ¹H NMR (CDCl₃) δ: 0.53 (3H, s, H-18), 0.85 (3H, d, J=6.5Hz, H-21), 1.21 (6H, s, H-26, 27), 2.17 (2H, m, H-4, 10), 2.62 (1H, dd,J=12.8, 4.4 Hz, H-4), 2.80 (1H, m, H-9), 2.85 (1H, dd, J=14.2, 4.2 Hz,H-10), 3.70-3.80 (2H, m, H-3, CH ₂ OH), 3.83 (1H, m, CH₂OH), 4.06 (1H,m, H-1), 5.82 (1H, d, J=11.2 Hz, H-7), 6.39 (1H, d, J=11.2 Hz, H-6). UVλmax (EtOH): 245, 253, 262 nm.

20-Epi-YI-7b: ¹H NMR (CDCl₃) δ: 0.55 (3H, s, H-18), 0.85 (3H, d, J=6.4Hz, H-21), 1.21 (6H, s, H-26, 27), 2.33 (1H, dm, J=13.5 Hz, H-4), 2.44(1H, br. d, J=13.5 Hz, H-4), 2.79 (1H, m, H-9), 3.12 (1H, dd, J=13.0,4.0 Hz, H-10), 3.63 (1H, m, H-1), 3.74-3.84 (2H, m, CH₂O H), 4.00 (1H,m, H-3), 5.88 (1H, d, J=11.2 Hz, H-7), 6.26 (1H, d, J=11.2 Hz, H-6). UVλmax (EtOH): 244, 252, 262 nm.

Example 48 (1,4-cis)-and(1,4-trans)-3,5-bis-[(t-butyldimethylsilyl)oxy]-4-hydroxy-4-methyl-cyclohexanolbenzyl ether (Compound 125)

To a stirred suspension of LiAlH, (237 mg, 6.24 mmol) in dry THF (5 mL)was added a solution of Compound 8 (2.99 g, 6.24 mmol, a mixture of ca.9:1) in dry THF (15 mL and the mixture was stirred for 2.5 h at roomtemperature. An additional LiAlH₄ (96 mg, 2.53 mmol) was added, and thewhole mixture was further stirred for 3.5 h. Excess LiAlH₄ was destroyedby adding an aqueous solution of saturated potassium sodium tartrate,and the mixture was extracted with AcOEt. The organic layer was washedwith saturated brine, dried over anhydrous MgSO₄, and evaporated invacuo. The residue was purified by silica gel column chromatography (80g; 50% AcOEt/hexane) to afford the major isomer 125 (1.81 g, 60%) in twostereoisomers, and the minor isomer was not isolated. It was impossibleto know whether the major product was 1,4-cis-isomer or1,4-trans-isomer,

125: ¹H NMR (CDCl₃) δ: 0.042 (6H, s, Si-Me×2), 0.062, 0.082 (each 3H, s,Si-Me×2), 0.84, 0.90 (each 9H, s, Si-tBu×2), 1.17 (3H, s, Me), 1.66 (1H,m), 1.88 (2H, m), 2.00 (1H, m), 2.19 (1H, s, OH), 3.70 (2H, m), 3.81(1H, m), 4.51, 4.54 (each 1H, d, J=12.0 Hz, CH₂Ph), 7.26-7.35 (5H, m,arom H).

Example 49 (1,4-cis)- or(1,4-trans)-3,5-bis-[(t-butyldimethylsilyl)oxy]-4-[(trimethylsilyl)oxy]-4-methyl-cyclohexanolbenzyl ether (Compound 126)

To a solution of Compound 125 (62.3 mg, 0.130 mmol, single main isomer)in dry toluene (2 mL) cooled to −78° C. were added Et₃N (72 μL, 0.516mmol) and trimethylsilyl trifluoromethanesulfonate (52 μL, 0.260 mmol),and the reaction mixture was stirred, and allowed to warm to −20° C. ina period of ca. 2.5 h. The mixture was poured into a 5% NaHCO₃ aqueoussolution, and extracted with AcOEt. The AcOEt layer was washed withsaturated brine, dried over anhydrous MgSO₄, and evaporated in vacuo.The residue was purified by silica gel column chromatography (5 g; 5%AcOEt/hexane) to yield Compound 126 (66.7 mg, 93%).

126: ¹H NMR (CDCl₃) δ: 0.018, 0.023, 0.04, 0.05 (each 3H, s, Si-Me×4),0.11 (9H, s, Si-Me₃), 0.83, 0.91 (each 9H, s, Si-tBu×2), 1.20 (3H, s,Me), 1.77 (2H, m), 1.89 (2H, m), 3.56-3.66 (3H, m), 4.52 (2H, s, CH₂Ph),7.26-7.35 (5H, m, arom. H). MS m/z (%): no M⁺, 537 (1), 495 (9), 461(3), 387 (87), 91 (100).

Example 50 (1,4-cis)- or(1,4-trans)-3,5-bis-[(t-butyldimethylsilyl)oxy]-4-[(trimethylsilyl)oxy]-4-methyl-cyclohexanol(Compound 127)

A mixture of Compound 126 (66.7 mg, 0.121 mmol, single main isomer) andpalladium, 10 wt. % on carbon (6.7 mg) in AcOEt (2 mL) and EtOH (1 mL)was hydrogenated under an atmospheric pressure of H₂ at roomtemperature. After vigorous stirring for 22 h, the reaction mixture wasfiltered through a pad of Celite. The pad was washed with EtOH andAcOEt, and the combined filtrate was concentrated in vacuo. The residuewas purified by silica gel column chromatography (6 g; 10% AcOEt/hexane)to afford Compound 127 (54.0 mg, 97%).

127: ¹H NMR (CDCl₃) δ: 0.044, 0.055, 0.063, 0.070 (each 3H, s, Si-Me×4),0.12 (9H, s, Si-Me₃), 0.88, 0.91 (each 9H, s, Si-tBu×2), 1.22 (3H, s,Me), 1.70-1.90 (4H, m), 3.58 (1H, t, J=2.8 Hz), 3.68 (1H, dd, J=11.5,4.2 Hz), 3.92 (1H, m). MS m/z (%): no M⁺, 405 (3), 387 (100), 273 (25).

Example 51(3R,5R)-3,5-bis-[(t-butyldimethylsilyl)oxy]-4-[(trimethylsilyl)oxy]-4-methyl-cyclohexanone(Compound 128)

To a solution of oxalyl chloride (339 μL, 3.89 mmol, single main isomer)in dry CH₂Cl₂ (3 mL) cooled to −78° C. was added a solution of DMSO (552μL, 7.78 mmol) in dry CH₂Cl₂ (3 mL). After being stirred for 5 min, asolution of Compound 127 (1.50 g, 3.24 mmol) in dry CH₂Cl₂ (6 mL) wasadded. The reaction mixture was stirred for 15 min at −78° C., and Et₃N(2.26 mL, 16.2 mmol) was added. The whole mixture was warmed from −78°C. to room temperature over 1.5 h after which time it was quenched withice water, and extracted with CH₂Cl₂. The CH₂Cl₂ extract was washed withsaturated brine, dried over anhydrous MgSO₄, and evaporated in vacuo.The residue was purified by silica gel column chromatography (30 g; 5%AcOEt/hexane) to afford Compound 128 (1.36, 91%) as a single compound.

128: ¹H NMR (CDCl₃) δ: 0.045-0.058 (12H, Si-Me×4), 0.15 (9H, s, Si-Me₃),0.84, 0.90 (each 9H, s, Si-tBu×2), 1.35 (3H, s, Me), 2.16 (1H, dt,J=14.6, 2.5 Hz), 2.37 (1H, ddd, J=14.0, 5.0, 2.1 Hz) 2.68 (1H, dd,J=14.0, 11.3 Hz), 2.93 (1H, dd, J=14.6, 3.1 Hz), 3.80 (1H, t, J=3.1 Hz),3.98 (1, dd, J=11.3, 5.0 Hz). MS m/z (%): no M⁺, 445 (5), 403 (87), 313(19), 271 (56), 143 (100).

Example 52 (aS*,3R,5R)-and(aR*,3R,5R)-[3,5-bis-[(t-butyldimethylsilyl)oxy]-4-[(trimethylsilyl)oxy]-4-methyl-cyclohexylidene]-methylacetate (Compound 129)

To a solution of diisopropylamine (0.827 mL, 5.90 mmol) in dry THF (5mL) cooled to −78° C. was added n-BuLi (3.73 mL, 5.90 mmol, 1.58 Msolution in hexane). After stirring for 15 min, to the solution wasadded methyl (trimethylsilyl)acetate (0.969 mL, 5.90 mmol). Afterstirring for 10 min, to this solution was slowly added a solution ofCompound 128 (1.36 g, 2.95 mmol, single compound) dissolved in dry THF(6 mL), and stirring was continued for 1 h at −78° C. The mixture wasquenched with a saturated NH₄Cl aqueous solution, and extracted withAcOEt. The organic phase was washed with saturated brine, and dried overanhydrous MgSO₄. Removal of the solvent in vacuo afforded the residue,which was purified by silica gel column chromatography (30 g; 2%AcOEt/hexane) to give Compound 129 (1.30 g, 85%) as a mixture of twostereoisomers. The ratio of the stereoisomers constituting the mixturewas ca. 1:1.

129: ¹H NMR (CDCl₃) δ: 0.02-0.073 (12H, Si-Me×4), 0.126, 0.130 (ca. 1:1)(9H, s, Si-Me₃), 0.81, 0.84 (ca. 1:1) (9H, s, Si-tBu), 0.91, 0.93 (ca.1:1) (9H, s, Si-tBu), 1.25 (3H, s, Me), 1.90-2.85 (4H), 3.60-3.84 (2H,m), 3.65, 3.68 (ca. 1:1) (3H, s, CO₂Me), 5.56, 5.71 (ca. 1:1) (1H, s,C═CH). MS m/z (%): 516 (M⁺, 1), 501 (4), 459 (100), 327 (46), 295 (61).

Example 53 (aS*,3R,5R)-and(aR*,3R,5R)-[3,5-bis-[(t-butyldimethylsilyl)oxy]-4-[(trimethylsilyl)oxy]-4-methyl-cyclohexylidene]-ethanol(Compound 130)

To a solution of Compound 129 (1.30 g, 2.51 mmol) in dry toluene (15 mL)cooled to −78° C. was added diisobutylaluminum hydride (7.53 mL, 7.53mmol, 1.0 M solution in toluene), and the mixture was stirred for 1.5 h.Excess reducing reagents were decomposed by adding an aqueous solutionof saturated potassium sodium tartrate. The mixture was poured into icewater, and extracted with AcOEt. The organic layer was successivelywashed with saturated brine, and dried over anhydrous MgSO₄. Solventswere evaporated in vacuo, and the residue was purified by silica gelcolumn chromatography (30 g; 10% AcOEt/hexane) to afford Compound 130(1.20 g, 98%) as a mixture of two stereoisomers in ca. 1:1 ratio.

130: ¹H NMR (CDCl₃) δ: 0.03-0.07 (12H, Si-Me×4), 0.12 (9H, s, Si-Me₃),0.85 (9H, s, Si-tBu), 0.91, 0.92 (ca. 1:1) (9H, s, Si-tBu), 1.23 (3H, s,Me), 1.85-2.75 (4H), 3.56-3.67 (2H, m), 4.08-4.14 (2H, m), 5.36, 5.49(ca. 1:1) (1H, m, C═CH). MS m/z (%): 488 (M⁺, 3), 470 (5), 455 (4), 431(10), 413 (54), 380 (9), 341 (17), 299 (23), 73 (100).

Example 54 (aS*,3R,5R)-and(aR*,3R,5R)-[3,5-bis-[(t-butyldimethylsilyl)oxy]-4-[(trimethylsilyl)oxy]-4-methyl-cyclohexylidene]ethyldiphenylphosphineoxide (Compound 118)

To a solution of Compound 130 (712 mg, 1.46 mmol, a mixture of ca. 1:1)in dry THF (10 mL) cooled to 0° C. were added n-BuLi (1.16 mL, 1.83mmol, 1.58 M solution in hexane) and a solution of p-toluenesulfonylchloride (349 mg, 1.83 mmol) in dry THF (1.5 mL) in this order, and themixture was stirred for 5 min. To this solution of the tosylate wasadded a red solution freshly prepared from diphenylphosphine (0.506 mL,2.91 mmol) in THF (3 mL) and n-BuLi (1.84 mL, 2.91 mmol, 1.58 M solutionin hexane) at 0° C. until the orange color persisted. The entire mixturewas stirred for 30 min at 0° C., and quenched by adding water (0.3 mL).The solvent was evaporated in vacuo, and the crude product was dissolvedin CH₂Cl₂ (8 mL). To this mixture was added a 10% hydrogen peroxideaqueous solution (12 mL). The mixture was stirred for 1 h at 0° C., andCH₂Cl₂ phase was separated. The organic layer was successively washedwith a 2N Na₂SO₃ aqeous solution and saturated brine, and dried overanhydrous MgSO₄. After evaporation of the solvent, the residue waspurified by silica gel column chromatography (20 g; 30-60% AcOEt/hexane)to afford Compound 118 (717 mg, 73%) as a mixture of two stereoisomersin a ratio of ca. 1:1.

118: ¹H NMR (CDCl₃) δ: −0.04-0.02 (12H, Si-Me×4), 0.07, 0.08 (ca. 1:1)(9H, s, Si-Me₃), 0.80, 0.83 (ca. 1:1) (9H, s, Si-tBu), 0.88, 0.89 (ca.1:1) (9H, s, Si-tBu), 1.17, 1.18 (ca. 1:1) (3H, s, Me), 1.6-2.6 (4H, m),2.9-3.2 (2H, m), 3.45-3.64 (2H, m), 5.17, 5.27 (ca. 1:1) (1H, m, CH═C),7.4-7.8 (10H, m, arom. H).

Example 55 (aS*,3R, 5R)-and (aR*,3R,5R)-[3,5-bis-[(t-butyldimethylsilyl)oxy]-4-[(t-butyldimethylsilyl)oxy]-ethylidene]-cyclohexanol(Compound 132)

A mixture of Compound 33b (384 mg, 0.633 mmol, more polar isomer) andpalladium, 10 wt. % on carbon (40 mg) in EtOH (5 mL) was hydrogenatedunder an atmospheric pressure of H₂ at room temperature. After vigorousstirring for 2.5 h, the reaction mixture was filtered through a pad ofCelite. The pad was washed with EtOH and AcOEt, and the combinedfiltrate was evaporated in vacuo. The organic layer was washed withsaturated brine, and dried over anhydrous MgSO₄. The residue waspurified by silica gel column chromatography (15 g; 5% AcOEt/hexane) toafford Compound 132b (298 mg, 91%). It was impossible to know whetherCompound 132b was aS*,3R,5R isomer or aR*,3R,5R isomer.

The compound 33a (800 mg, 1.32 mmol, less polar isomer) was hydrogenatedby catalytic reduction to thereby gave Compound 132 (536 mg, 79%) as amixture of 132a: 132b=ca. 2:1 ratio. It was impossible to know whetherCompound 132b was aS*,3R,5R isomer or aR*,3R,5R isomer. It wasimpossible to-know whether Compound 132a was aS*,3R,5R isomer oraR*,3R,5R isomer. (Under catalytic reduction conditions using less polarisomer, isomerization at C-1 position occurred to give 132b.)

132a (less polar isomer): ¹H NMR (CDCl₃) δ: 0.06 (6H, s, Si-Me×2), 0.07,0.087, 0.094, 0.12 (each 3H, s, Si-Me×4), 0.89 (18H, s, Si-tBu×2), 0.93(9H, s, Si-tBu), 1.46-1.6 (2H, m), 2.12 (1H, m), 2.32 (1H, m), 4.11 (1H,m, H-1), 4.20 (1H, ddd, J=12.8, 6.2, 1.1 Hz, CH₂OTBS), 4.28 (1H, ddd,J=12.8, 8.0, 1.1 Hz, CH₂OTBS), 4.82 (1H, m), 5.05 (1H, m), 5.66 (1H, m,C═CH). MS m/z (%): no M⁺, 501 (1), 459 (36), 441 (18), 384 (5), 367(24), 327 (83), 309 (4), 73 (100).

132b (more polar isomer): ¹H NMR (CDCl₃) δ: 0.02, 0.058, 0.064, 0.067,0.073, 0.075 (each 3H, s, Si-Me×6), 0.87, 0.89, 0.92 (each 9H, s,Si-tBu×3), 1.43-1.51 (2H, m), 2.01-2.06 (1H, m), 2.12-2.18 (1H, m), 4.19(1H, m, H-1), 4.27 (1H, ddd, J=13.1, 6.5, 0.9 Hz, CH₂OTBS), 4.37 (1H,ddd, J=13.1, 5.7, 0.9 Hz, CH₂OTBS), 4.48, 4.86 (each 1H, m, H-3, 5),5.56 (1H, m, C═CH). MS m/z (%): no M⁺, 459 (37), 441 (22), 384 (3), 367(8), 327 (100), 309 (5), 72 (94).

Example 56[3,5-bis-[(t-butyldimethylsilyl)oxy]-4-[(t-butyldimethylsilyl)oxy]-ethylidene]-cyclohexanone(Compound 133)

To a solution of oxalyl chloride (7.5 μL, 0.086 mmol) in dry CH₂Cl₂,(0.2 mL) cooled to −78° C. was added a solution of DMSO (12.2 μL, 0.172mmol) in dry CH₂Cl₂ (100 μL). After being stirred for 5 min, a solutionof Compound 132b (37 mg, 0.072 mmol, more polar isomer) in dry CH₂Cl₂(0.4 mL) was added. The reaction mixture was stirred for 15 min at −78°C., and Et₃N (50 μL, 0.358 mmol) was added. The whole mixture wasallowed to warm to room temperature over a period of 1 h at which pointthe reaction was quenched with ice water, and extracted with CH₂Cl₂. TheCH₂Cl₂ extract was washed with saturated brine, and dried over anhydrousMgSO₄. Solvents were evaporated in vacuo, and the residue was purifiedby silica gel column chromatography (3 g; 3% AcOEt/hexane) to affordCompound 133 (36.6 mg, 99%) as a single compound.

The compound 133 (69 mg, 96%) was prepared from Compound 132a (72.5 mg,0.140 mmol, less polar isomer) by Swern oxidation method.

133: ¹H NMR (CDCl₃) δ: 0.02, 0.06, 0.08, 0.09 (each 3H, s, Si-Me×4),0.07 (6H, s, Si-Me×2), 0.84, 0.90, 0.91 (each 9H, s, Si-tBu×3), 2.36(1H, dd, J=14.2, 10.2 Hz), 2.46 (1H, dd, J=14.4, 3.3 Hz), 2.51 (1H, ddd,J=14.4, 3.6, 1.9 Hz), 2.75 (1H, ddd, J=14.2, 5.6, 1.8 Hz), 4.34 (2H, m,CH₂OTBS), 4.76 (1H, m), 5.04 (1H, t, J=3.4 Hz), 5.81 (1H, m, C═CH). MSm/z (%): no M⁺, 457 (100), 325 (38), 193 (13).

Example 57 (aS*,3R,5R)-and(aR*,3R,5R)-[3,5-bis-[(t-butyldimethylsilyl)oxy]-4-[2-butyldimethylsilyl)oxy]-ethyl-cyclohexylidene]-methylacetate (Compound 134)

To a solution of diisopropylamine (0.385 mL, 2.64 mmol) in dry THF (4mL) cooled to −78° C. was added n-BuLi (1.67 mL, 2.64 mmol, 1.58 Msolution in hexane). After stirring for 15 min, to the solution wasadded methyl (trimethylsilyl)acetate (0.433 mL, 2.64 mmol). After beingstirred for 10 min, to this solution was slowly added a solution ofCompound 133 (680 mg, 1.32 mmol) in dry THF (8 mL), and stirring wascontinued for 1 h at −78° C. after which time it was quenched with asaturated NH₄Cl aqueous solution, and extracted with AcOEt. The organicphase was washed with saturated brine, dried over anhydrous MgSO₄, andevaporated in vacuo. The residue was purified by silica gel columnchromatography (15 g; 2% AcOEt/hexane) to give Compound 134 (699 mg,93%) as a mixture of two stereoisomers in ca. 3:1 ratio. It wasimpossible to know whether the major product was aS*,3R;5R isomer oraR*,3R,5R isomer.

134: ¹H NMR (CDCl₃) δ: 0.04-0.12 (18H, s, Si-Me×6), 0.80-0.93 (27H, s,Si-tBu×3), 3.67, 3.70 (ca. 1:3) (3H, s, CO₂Me), 3.90, 4.02 (ca. 1:3)(1H, m), 4.25-4.55 (4H, m), 4.87 (1H, m), 5.6-5.8 (2H, m, C═CH×2). MSm/z (%): no M⁺, 555 (3), 513 (79), 438 (33), 381 (100), 349 (8), 249(6).

Example 58 (aS*,3R,5R)-and(aR*,3R,5R)-[3,5-bis-[(t-butyldimethylsilyl)oxy]-4-[2-butyldimethylsilyl)oxy]-ethyl-cyclohexylidene]-ethanol(Compound 135)

To a solution of Compound 134 (699 mg, 1.22 mmol, a mixture of ca. 3:1)in dry toluene (6 mL) cooled to −78° C. was added diisobutylaluminumhydride (3.66 mL, 3.66 mmol, 1.0 M solution in toluene), and the mixturewas stirred for 1 h. Excess reagents were decomposed by adding anaqueous solution of saturated potassium sodium tartrate, and the mixturewas poured into ice water, and then extracted with AcOEt. The organiclayer was washed with saturated brine, and dried over anhydrous MgSO₄.Solvents were evaporated in vacuo, and the residue was purified bysilica gel column chromatography (10 g; 5% AcOEt/hexane) to affordCompound 135 (567 mg, 85%) as a mixture of two stereoisomers in ca. 3:1ratio. It was impossible to know whether the major product was aS*,3R,5Risomer or aR*,3R,5R isomer.

135: ¹H NMR (CDCl₃) δ: 0.06-0.07 (18H, Si-Me×6), 0.85-0.92 (27H,Si-tBu×3), 194-2.77 (4H, m), 4.0-4.4 (5H, m), 4.77, 4.90 (ca. 3:1) (1H,m), 5.50, 5.71 (ca. 3:1) (1H, m, C═CH), 5.60, 5.66 (ca. 3:1) (1H, m,C═CH).

Example 59 (aS*,3R,5R)-and(aR*,3R,5R)-[3,5-bis-[(t-butyldimethylsilyl)oxy]-4-[2-(t-butyldimethylsilyl)oxy]-ethyl-cyclohexylidene]ethyldiphenylphosphineoxide (Compound 119)

To a solution of Compound 135 (164 mg, 0.302 mmol, a mixture of ca. 3:1)in dry THF (1.5 mL) cooled to 0° C. were added n-BuLi (228 μL, 0.360mmol, 1.58 M solution in hexane) and a solution of p-toluenesulfonylchloride (68.6 mg, 0.360 mmol) in dry THF (0.5 mL) in this order, andthe mixture was stirred for 5 min. To this solution of the tosylate wasslowly added a red solution freshly prepared from diphenylphosphine (105μL, 0.604 mmol) in THF (0.5 mL) and n-BuLi (382 μL, 0.604 mmol, 1.58 Msolution in hexane) at 0° C. until the orange color persisted. Theentire mixture was stirred for 30 min at 0° C., and quenched by addingwater (0.1 mL). The solvent was evaporated in vacuo and the crudeproduct was dissolved in CH₂Cl₂ (3 mL). To this mixture was added 10%hydrogen peroxide (4 mL). The mixture was stirred for 1 h at 0° C. andCH₂Cl₂ phase was separated. The organic layer was successively washedwith a 2N Na₂SO₃ aqueous solution, water and saturated brine, and driedover anhydrous MgSO₄ After evaporation of the solvent, the residue waspurified by silica gel column chromatography (7 g; 50% AcOEt/hexane) toafford Compound 119 (139 mg, 63%) as a mixture of two stereoisomers.Most of the ¹H NMR signals from two isomers were overlapped each other,and the ratio of the two isomers was not determined.

119: ¹H NMR (CDCl₃ δ: −0.02-0.05 (18H, Si-Me×6), 0.80-0.90 (27H,Si-tBu×3), 1.90-2.60 (4H, m), 3.15 (2H, m, CH₂PO), 4.20-4.38 (3H, m),4.71 (H, m), 5.29 (1H, m, C═CH), 5.56 (1H, m, CH═C), 7.40-7,80 (10H, m,arom H).

Example 60 22-Ene-25-hydroxy Grundmann's ketone (Compound 120)

22-Ene-25-hydroxy Grundmann's ketones (120a, b) were synthesized asshown in the scheme.

Synthesis of 5-carbon synthon (V)

Compound (VI) was synthesized starting from commercially availablevitamin D₂ employing the literature methods (Fernandez, B., Perez, J. A.M., Granja, J. R., Castedo, L., Mourino, A., J. Org. Chem., 1992, 57,3173-3178 and Fall, Y., Vitale, C., Mourino, A., Tetrahedron Lett.,2000, 41, 7337-7340).

p-Toluenesulfonic acid monohydrate (1.69 g, 8.893 mmol) was added to asolution of the compound VI (1.17 g, 2.964 mmol) in MeOH (15 mL) cooledto 0° C., and the reaction mixture was stirred at 0° C. for 16 h and atroom temperature for 8 h. The mixture was diluted with AcOEt, and theorganic layer was successively washed with a 5% NaHCO₃ aqueous solutionand saturated brine, and dried over anhydrous MgSO₄. Evaporation of thesolvent gave the residue, which was purified by silica gel columnchromatography (30 g; 30% AcOEt/hexane) to afford the compound VII(790.7 mg, 95%).

VII: ¹H NMR (CDCl₃) δ: 0.93 (3H, s, H-18), 1.01 (3H, d, J=6.6 Hz, H-21),1.20 (6H, s, H-26, 27), 4.08 (1H, m, H-8), 5.37 (2H, m), H-22, 23).

To a solution of oxalyl chloride (127 μL, 1.459 mmol) in dry CH₂Cl₂ (1mL) cooled to −78° C. was added a solution of DMSO (206 μL, 2.917 mmol)in dry CH₂Cl₂ (0.5 mL). After being stirred for 10 min, a solution ofthe compound VII (186 mg, 0.663 mmol) in dry CH₂Cl₂ (2 mL) was added.The reaction mixture was stirred for 15 min at −78° C., and Et₃N (924μL, 6.63 mmol) was added. The whole mixture was warmed from −78° C. to0° C. at which point the reaction was quenched with ice water, andextracted with CH₂Cl₂. The CH₂Cl₂ extract was washed with saturatedbrine, dried over anhydrous MgSO₄, and evaporated to dryness. Theresidue was purified by silica gel column chromatography (7 g; 25%AcOEt/hexane) to afford the compound VIII (178.0 mg, 96%).

VIII: ¹H NMR (CDCl₃) δ: 0.67 (3H, s, H-18), 1.07 (3H, d, J=6.6 Hz,H-21), 1.20 (6H, s, H-26, 27), 5.37 (2H, m, H-22, 23).

To a solution of the compound VIII (178.0 mg, 0.639 mmol) in dry CH₂Cl₂(2 mL) cooled to 0° C. was added diisopropylethylamine (557 μL, 3.196mmol) followed by chloromethyl methyl ether (121 μL, 1.596 mmol). Afterstirring for 3 h at room temperature, additional diisopropylethylamine(111 μL, 0.639 mmol) and chloromethyl methyl ether (24 μL, 0.320 mmol)were added, and the whole mixture was further stirred at roomtemperature for 1.5 h. The mixture was poured into ice water, andextracted with CH₂Cl₂. The organic phase was successively washed with 5%NaHCO₃ and saturated brine, and dried over anhydrous MgSO₄. Evaporationof the solvent afforded a residue, which was purified by silica gelcolumn chromatography (7 g; 10% AcOEt/hexane) to give Compound 120a(154.2 mg, 75%).

120a: ¹H NMR (CDCl₃) δ: 0.65 (3H, s, H-18), 1.05 (3H, d, J=6.7 Hz,H-21), 1.19 (6H, s, H-22, 23).

To a solution of the compound VIII (710.4 mg, 2.55 mmol) in dry DMF (10mL) cooled to 0° C. were added imidazole (520.8 mg, 7.65 mmol) followedby chlorotriethylsilane (868 μL, 5.10 mmol). After being stirred for 2.5h, the reaction mixture was poured into ice water, and extracted withAcOEt-hexane (v/v, 1:1). The organic phase was washed with saturatedbrine, and dried over anhydrous MgSO₄. Solvents were evaporated invacuo, and the residue was purified by silica gel column chromatography(30 g; 4% AcOEt/hexane) to give Compound 120b (887.5 mg, 89%).

120b: ¹H NMR (CDCl₃) δ: 0.57 (6H, q, J=7.9 Hz, SiCH₂×3), 0.66 (3H, s,H-18), 0.95 (9H, t, J=7.9 Hz, SiCH₂CH₃×3), 1.05 (3H, d, J=6.7 Hz, H-21),1.16 (6H, s, H-26, 27), 2.45 (1H, dd, J=11.0, 7.5 Hz, H-9), 5.24, 5.40(each 1H, m, H-22, 23).

Example 61 22-Oxa-25-hydroxy Grundmann's ketone (Compound 121)

22-Oxa-25-hydroxy Grundmann's ketone (121) was synthesized as shown inthe scheme.

Synthesis of 5-carbon synthon (XI)

The compound X was prepared from vitamin D₂ according to the publishedmethods (Posner, G. H., Lee, J. K., White, M. C., Hutchings, R. H., Dai,H., Kachinski, J. L., Dolan, P., Kensler, T. W., J. Org. Chem., 1997,62, 3299-3314).

To a solution of the compound X (800 mg, 2.56 mmol) and the compound XI(4.77 g, 12.80 mmol) in dry DMF (30 mL) was added NaH (3.07 g, 76.77mmol, 60% paraffin liquid), and the resulting suspension was stirred atroom temperature for 16 h. The whole mixture was poured into ice water,and extracted with AcOEt-hexane. (v/v, 1:1). The organic layer waswashed with saturated brine, and dried over anhydrous MgSO₄. Afterevaporation of the solvent, the residue was purified by silica gelcolumn chromatography (85 g; 1% AcOEt/hexane) to yield the compound XII(1.135 g, 86%).

XII: ¹H NMR (CDCl₃) δ: −0.01, 0.01, 0.06, 0.07 (each 3H, s, Si-Me×4),0.85, 0.89 (each 9H, s, Si-tBu×2), 0.93 (3H, s, H-18), 1.05 (3H, d,J=6.0 Hz, H-21), 1.21, 1.22 (each 3H, s, H-26, 27), 3.27 (1H, m, H-20),3.31, 3.68 (each 1H, m, H-23), 4.00 (1H, m, H-8). MS m/z (%): 512 (noM⁺), 455 (1), 497 (1), 380 (1), 323 (3), 295 (20), 237 (100), 163 (89),75 (81).

A mixture of the compound XII (1.13 g, 2.20 mmol) and p-toluenesulfonicacid monohydrate (2.10 g, 11.01 mmol) in MeOH (10 mL) was stirred atroom temperature for 8 h. The mixture was diluted with AcOEt, and theorganic phase was successively washed with a 5% NaHCO₃ aqueous solutionand saturated brine, and dried over anhydrous MgSO₄. Evaporation of thesolvent gave the residue, which was purified by silica gel columnchromatography (30 g; 30% AcOEt/hexane) to afford the compound XIII(610.2 mg, 97%).

XIII: ¹H NMR (CDCl₃) δ: 0.95 (3H, s, H-18), 1.11 (3H, d, J=6.0 Hz,H-21), 1.23, 1.24 (each 3H, s, H-26, 27), 3.30 (1H, m, H-20), 3.46 (1H,m, H-23), 3.59 (1H, s, OH), 3.85 (1H, dt, J=9.5, 4.1 Hz, H-23), 4.09(1H, m, H-8). MS m/z (%): 248 (M⁺, 2), 226 (1), 197 (6), 181 (21), 163(84), 113 (45), 69 (100).

To a mixture of the compound XIII (742.7 mg, 2.611 mmol),4-methylmorpholine N-oxide (2.14 g, 18.28 mmol) and Molecular sieves, 4A(450 mg) in dry CH₂Cl₂ (15 mL) was added tetrapropylammoniumperruthenate (Pr₄NRuO₄, 45.9 mg, 0.131 mmol), and the whole mixture wasstirred at room temperature for 1 h. The reaction mixture was directlyloaded onto silica gel column (30 g). The column was eluted with 50%AcOEt/hexane to give the compound XIV (722.8 mg, 98%).

XIV: ¹H NMR (CDCl₃) δ: 0.65 (3H, s, H-18), 1.15 (3H, d, J=5.9 Hz, H-21),1.24, 1.25 (each 3H, s, H-26, 27), 2.47 (1H, m, H-9), 3.25 (1H, m,H-20), 3.45 (1H, m, H-23), 3.44 (1H, s, OH), 3.88 (1H, dt, J=9.6, 4.2Hz, H-23). MS m/z (%): 282 (M⁺, 1), 264 (2), 195 (23), 179 (69), 161(41), 113 (29), 69 (100).

Imidazole (1.04 g, 15.30 mmol) followed by chlorotriethylsilane (1.3 mL,7.65 mmol) was added to a solution of the compound XIV (720.2 mg, 2.550mmol) in dry DMF (10 mL) cooled to 0° C. The reaction mixture wasallowed to warm to room temperature, and stirred for 2 h, poured intoice water, and extracted with AcOEt-hexane (v/v, 1:1). The organic layerwas washed with saturated brine, dried over anhydrous MgSO₄, andevaporated in vacuo. The residue was purified by silica gel columnchromatography (35 g; 2% AcOEt/hexane) to yield Compound 121 (1.005 g,99%).

121: ¹H NMR (CDCl₃) δ: 0.57 (6H, q, J=7.9 Hz, SiCH₂×3), 0.65 (3H, s,H-18), 0.94 (9H, t, J=7.9 Hz, SiCH₂CH₃×3), 1.10 (3H, d, J=5.9 Hz, H-21),1.22, 1.24 (each 3H, s, H-26, 27), 2.45 (1H, dd, J=11.0, 7.5 Hz, H-14),3.24 (1H, m, H-20), 3.31, 3.73 (each 1H, m, H-23).

Example 62 24a,26a,27a-Trihomo-22,24-diene-25-hydroxy Grundmann's ketone(Compound 122)

24a,26a,27a-Trihomo-22,24-diene-25-hydroxy Grundmann's ketone (Compound122) was synthesized according to the published methods (Posner, G. H.,Lee, J. K., White, M. C., Hutchings, R. H., Dai, H., Kachinski, J. L.,Dolan, P., Kensler, T. W., J. Org. Chem., 1997, 62, 3299-3314).

Synthesis of Wittig-Horner Reagent (XV)

Example 63 1α-[(t-butyldimethylsilyl)oxy]-2α-[(trimethylsilyl)oxy]-and1α-[(t-butyldimethylsilyl)oxy]-2β-[(trimethylsilyl)oxy]-22-ene-25-[(methoxymethyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 136a and 136b)

To a solution of A-ring phosfine oxide 22 (268.2 mg, 0.407 mmol, amixture of ca. 2:1) in dry THF (2 mL) cooled to −78° C. was added slowlyn-BuLi (261 μL, 0.407 mmol, 1.56 M solution in hexane), and theresulting dark orange solution was stirred for 15 min. To this coloredsolution was added a solution of C/D-ring ketone 120a (87.5 mg, 0.271mmol) in dry THF (1 mL), the reaction mixture was stirred for 2 h at−78° C., quenched with a saturated NH₄Cl aqueous solution, and extractedwith AcOEt. The AcOEt layer was washed with saturated brine, dried overanhydrous MgSO₄, and evaporated in vacuo. The residue was purified bysilica gel column chromatography (10 g; 2% AcOEt/hexane) to affordCompound 136 (116.1 mg, 56%) as a mixture of two stereoisomers. Theratio of the isomers 136a and 136b constituting the mixture was ca. 5:4.An elution of 10% AcOEt/hexane gave the unreacted starting material 120a(11.6 mg).

NMR Data of the Mixture

136a (major product): ¹H NMR (CDCl₃) δ: 0.04-0.06 (12H, s, Si-Me×4),0.12 (9H, s, Si-Me×3), 0.55 (3H, s, H-18), 0.87, 0.88 (each 9H, s,Si-tBu×2), 1.02 (3H, d, J=6.6 Hz, H-21), 1.20 (6H, s, H-26, 27), 2.80(1H, m, H-9), 3.37 (3H, s, OMe), 3.54 (1H, m, H-2), 3.80 (1H, m, H-3),3.87 (1H, m, H-1), 4.73 (2H, s, OCH₂O), 5.33 (2H, m, H-22, 23), 5.81(1H, d, J=11.1 Hz, H-7), 6.10 (1H, d, J=11.1 Hz, H-6).

136b (minor product): ¹H NMR (CDCl₃) δ: 0.04-0.06 (12H, s, Si-Me×4),0.12 (9H, s, Si-Me×3), 0.54 (3H, s, H-18), 0.86, 0.89 (each 9H, s,Si-tBu×2), 1.02 (3H, d, J=6.6 Hz, H-21), 1.02 (6H, s, H-26, 27), 2.80(1H, m, H-9), 3.37 (3H, s, OMe), 3.60 (1H, m, H-2), 3.80 (1H, m, H-3),3.93 (1H, m, H-1), 4.73 (2H, s, OCH₂O), 5.33 (2H, m, H-22, 23), 5.79(1H, d, J=11.2 Hz, H-7), 6.13 (1H, d, J=11.2 Hz, H-6). MS m/z (%) of themixture: 762 (M⁺, 18), 700 (28), 630 (39), 568 (57), 511 (18), 465 (25),309 (36), 147 (35), 109 (56), 75 (100).

Example 64 1α-[(t-butyldimethylsilyl)oxy]-2β-hydroxy-and1α-[(t-butyldimethylsilyl)oxy]-2β-hydroxy-22-ene-25-[(methoxymethyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 137a and 137b)

A solution of Compound 136 (60.0 mg, 0.0786 mmol, 136a:136b=ca. 5:4) inTHF-AcOH—H₂O (v/v/v, 8:8: 1, 4.25 mL) was stirred at room temperaturefor 18 h, and diluted with AcOEt. The organic phase was successivelywashed with a 5% NaHCO₃ aqueous solution and saturated brine, and driedover Na₂SO₄. After evaporation of the solvent, the resulting residue waspurified by silica gel column chromatography (6 g;, 5% AcOEt/hexane) toafford Compound 137 (53.4 mg, 98%) as a mixture of two stereoisomers.The ratio of the isomers 137a and 137b constituting the mixture was ca.5:4.

NMR Data of the Mixture

137a (major product): ¹H NMR (CDCl₃) δ: 0.059-0.096 (12H, Si-Me×4), 0.56(3H, s, H-18), 0.87, 0.88 (each 9H, s, Si-tBu×2), 1.02 (3H, d, J=6.6 Hz,H-21), 1.20 (6H, s, H-26, 27), 2.80 (1H, m, H-9), 3.37 (3H, s, OMe),3.51 (1H, m, H-2), 3.90, (1H, m, H-3), 3.99 (1H, m, H-1), 4.73 (2H, s,OCH₂O), 5.33 (2H, m, H-22, 23), 5.79 (1H, d, J=11.1 Hz, H-7), 6.15 (1H,d, J=11.1 Hz, H-6).

137b (minor product): ¹H NMR (CDCl₃) δ: 0.06-0.10 (12H, Si-Me×4), 0.54(3H, s, H-18), 0.86, 0.90 (each 9H, s, Si-tBu×2), 1.02 (3H, d, J=6.6 Hz,H-21), 1.20 (6H, s, H-26, 27), 2.80 (1H, m, H-9), 3.37 (3H, s, OMe),3.59 (1H, m, H-2), 3.99 (2H, m, H-1, 3), 4.73 (2H, s, OCH₂O), 5.33 (2H,m, H-22, 23), 5.80 (1H, d, J=11.2 Hz, H-7), 6.18 (1H, d, J=11.2 Hz,H-6). MS m/z (%) of the mixture: 690 (M⁺, 6), 628 (9), 571 (7), 439(29), 309 (11), 109 (63) 75 (100).

Example 651α-[(t-butyldimethylsilyl)oxy]-2α-[2-(t-butyldimethylsilyl)oxy]-ethoxy]-and1α-[(t-butyldimethylsilyl)oxy]-2β-[2-(t-butyldimethylsilyl)oxy]-ethoxy]-22-ene-25-[(methoxymethyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 138a and 138b)

A suspension of Compound 137 (44.3 mg, 0.064 mmol, 137a:137b=ca. 5:4),NaH (77.0 mg, 1.925 mmol, 60% paraffin liquid), and(2-bromoethoxy)-tert-butyldimethylsilane (69 μl, 0.320 mmol) in dry DMF(1 mL) cooled to 0° C. was stirred vigorously for 20 h, and the reactionmixture was poured into ice water, and then extracted with AcOEt-hexane(v/v, 1:1). The organic phase was washed with saturated brine, and driedover anhydrous MgSO₄. Following evaporation of the solvent in vacuo, theresidue was purified by silica gel column chromatography (10 g; 2%AcOEt/hexane) to afford Compound 138 (45.0 mg, 83%) as a mixture of twostereoisomers. The ratio of the isomers 138a and 138b constituting themixture was ca. 1:1.

138: ¹H NMR (CDCl₃) δ: 0.05-0.09 (18H, Si-Me×6), 0.54, 0.56 (ca. 1:1)(3H, s, H-18), 0.86-0.91 (27H, Si-tBu×3), 1.02 (3H, d, J=6.6 Hz, H-21),1.24 (6H, s, H-26, 27), 2.80 (1H, m, H-9), 3.19, 3.28 (ca. 1:1) (1H, m,H-2), 3.37 (3H, s, OMe), 3.5-4.1 (7H, m, OCH₂CH₂O, H-1, 3), 4.73 (2H, s,OCH₂O), 5.32 (2H, m, H-22, 23), 5.79 (1H, H-7), 6.13 (1H, H-6). MS m/z(%): no M⁺, 786 (1), 716 (4), 654 (8), 610 (8), 553 (5), 522 (10), 465(12), 233 (60), 109 (28), 75 (100).

Example 66 1α,25-dihydroxy-2α-(2-hydroxyethoxy)-and1α,25-dihydroxy-2β-(2-hydroxyethoxy)-22-ene-19-norvitamin D₃ (Compounds101a and 101b)

A mixture of Compound 138 (45.0 mg, 0.053 mmol, 138a: 138b=ca. 1:1) andcamphor sulfonic acid (73.8 mg, 0.318 mmol) in dry MeOH (1 mL) wasstirred at room temperature for 2 h. The reaction mixture was pouredinto a 5% NaHCO₃ aqueous solution, and extracted with AcOEt. The organicphase was washed with saturated brine, dried over anhydrous MgSO₄, andevaporated in vacuo. The residue was purified by silica gel columnchromatography (4 g; 2% MeOH/AcOEt) to give Compound 101 (20.3 mg, 83%)as a mixture of ca. 1:1.

The mixture of Compounds 101 a and 101 b was separated by HPLC (YMC-PackODS-AM SH-342-5, 150×20 mm, 25% H₂O in MeOH) to afford Compounds 101a(8.3 mg) and 101b (7.9 mg), respectively.

101a: ¹H NMR (CDCl₃) δ: 0.57 (3H, s, H-18), 1.04 (3H, d, J=6.6 Hz,H-21), 1.20 (6H, s, H-26, 27), 2.67, 3.03, 3.33 (each 1H, br. s, OH×3),2.62 (1H, dd, J=13.5, 4.5 Hz, H-4), 2.79 (1H, m, H-9), 2.86 (1H, dd,J=14.4, 4.9 Hz, H-10), 3.33 (1H, dd, J=8.0, 2.8 Hz, H-2), 3.68-3.83 (4H,m, OCH₂CH₂O), 3.94 (1H, m, H-3), 4.15 (1H, m, H-1), 5.38 (2H, m, H-22,23), 5.82 (1H, d, J=11.2 Hz, H-7), 6.33 (1H, d, J=11.2 Hz, H-6). UV λmax(EtOH): 244 (ε 27,400), 252 (ε 32,000), 261 (ε 21,700) nm. MS m/z (%):462 (M⁺, 55), 444 (58), 426 (43), 408 (22), 346 (32), 317 (68), 299(39), 255 (69), 237 (76), 133 (100). HR-MS m/z: 462.3348 (Calcd forC₂₈H₄₆O₅: 462.3345).

101b: ¹H NMR (CDCl₃) δ: 0.56 (3H, s, H-18), 1.04 (3H, d, J=6.6 Hz,H-21), 1.20 (6H, s, H-26, 27), 2.34 (1H, br. d, J=14.2 Hz, H-4), 2.48(1H, dm, J=14.2 Hz, H-4), 2.62 (1H, br. s, OH), 2.79 (1H, m, H-9), 3.07(1H, dd, J=13.2, 3.8 Hz, H-10), 3.28 (1H, dd, J=8.7, 2.7 Hz, H-2), 3.28,3.42 (each 1H, br. s, OH×2), 3.64-3.87 (5H, m, OCH₂CH₂O, H-1), 4.17 (1H,m, H-3), 5.39 (2H, m, H-22, 23), 5.84 (1H, d, J=11.2 Hz, H-7), 6.27 (1H,d, J=11.2 Hz, H-6). UV λmax (EtOH): 243 (ε 27,700), 251 (ε 32,300), 261(ε 21,600) nm. MS m/z (%): 462 (M⁺, 41), 444 (44), 426 (37), 408 (17),346 (39), 317 (55), 299 (29), 255 (59), 237 (75), 133 (100). HR-MS m/z:462.3362 (Calcd for C₂₈H₄₆O₅: 462.3345).

Example 671α-[(t-butyldimethylsilyl)oxy]-2-oxo-22-ene-25-[(methoxymethyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether (Compound 139)

To a solution of oxalyl chloride (7.8 μL 0.088 mmol) in dry CH₂Cl₂ (1mL) cooled to −78° C. was added a solution of DMSO (12.4 μL, 0.175 mmol)in dry CH₂Cl₂ (0.2 mL). After being stirred for 5 min, a solution ofCompound 137 (50.4 mg, 0.073 mmol, 137a: 137b=ca. 5:4) in dry CH₂Cl₂(1.2 mL) was added. The reaction mixture was stirred for 15 min at −78°C., and Et₃N (51 μL, 0.365 mmol) was added. The whole mixture wasstirred at −78° C. for 40 min and at 0° C. for 20 min, quenched with icewater, and extracted with CH₂Cl₂. The CH₂Cl₂ extract was washed withsaturated brine, dried over anhydrous MgSO₄, and concentrated in vacuo.The residue was purified by silica gel column chromatography (5 g; 5%AcOEt/hexane) to afford Compound 139 (49.0 mg, 97%) as a singlecompound.

139: ¹H NMR (CDCl₃) δ: 0.055, 0.065, 0.069, 0.094 (each 3H, s, Si-Me×4),0.56 (3H, s, H-18), 0.88, 0.89 (each 9H, s, Si-tBu×2), 1.03 (3H, d,J=6.6 Hz, H-21), 1.20 (6H, s, H-26, 27), 2.44 (1H, dd, J=13.3, 8.9 Hz),2.52 (1H, dd, J=14.2, 3.8 Hz), 2.69 (2H, m), 2.81 (1H, m, H-9), 3.37(3H, s, OMe), 4.35 (1H, dd, J=6.4, 4.2 Hz), 4.55 (1H, dd, J=8.7, 5.5Hz), 4.73 (2H, s, OCH₂O), 5.34 (2H, m, H-22, 23), 5.80 (1H, d, J=11.2Hz, H-7), 6.34 (1H, d, J=11.2 Hz, H-6). MS m/z (%): no M⁺, 631 (5), 569(100), 437 (22), 325 (17), 109 (81), 75 (52).

Example 68 E-isomer and Z-isomer of1α-[(t-butyldimethylsilyl)oxy]-2-cyanomethylene-22-ene-25-[(methoxymethyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 140a and 140b)

To a solution of diethyl (cyanomethyl)phosphonate (32 μL, 0.197 mmol) indry THF (1 mL) cooled to −40° C. was added n-BuLi (126 μL, 0.197 mmol,1.56 M solution in hexane). The mixture was stirred for 15 min, and asolution of Compound 139 (68.0 mg, 0.099 mmol) in dry THF (1.2 mL) wasadded slowly. Stirring was continued for 2 h at −40° C. after which timethe reaction mixture was quenched with a saturated NH₄Cl aqueoussolution, and extracted with AcOEt. The AcOEt layer was washed withsaturated brine, and dried over anhydrous MgSO₄. Evaporation of thesolvent gave the residue, which was purified by silica gel columnchromatography (5 g; 3% AcOEt/hexane) to afford Compound 140 (59.6 mg,85%) as a mixture of two stereoisomers. The ratio of the isomers 140a(E-isomer) and 140b (Z-isomr) constituting the mixture was ca. 1:1.

NMR Data of the Mixture

140a: ¹H NMR (CDCl₃) δ: 0.054, 0.065, 0.094, 0.120 (each 3H, s,Si-Me×4), 0.56 (3H, s, H-18), 0.84, 0.92 (each 9H, s, Si-tBu×2), 1.02(3H, d, J=6.6 Hz, H-21), 1.20 (6H, s, H-26, 27), 2.80 (1H, m, H-9), 3.12(1H, m, H-10), 3.37 (3H, s, OMe), 4.46 (1H, m, H-1), 4.73 (2H, s,OCH₂O), 4.99 (1H, t, J=2.8 Hz, H-3), 5.33 (2H, m, H-22, 23), 5.47 (1H,d, J=1.8 Hz, C═CHCN), 5.82 (1H, d, J=11.1 Hz, H-7), 6.18 (1H, d, J=11.1Hz, H-6).

140b: ¹H NMR (CDCl₃) δ: 0.065, 0.075, 0.111, 0.133 (each 3H, s,Si-Me×4), 0.55 (3H, s, H-18), 0.84, 0.92 (each 9H, s, Si-tBu×2), 1.02(3H, d, J=6.6 Hz, H-21), 1.20 (6H, s, H-26, 27), 2.80 (1H, m, H-9), 2.99(1H, m, H-10), 3.37 (3H, s, OMe), 4.57 (1H, m, H-3), 4.73 (2H, s,OCH₂O), 5.04 (1H, t, J=2.8 Hz, H-1), 5.33 (2H, m, H-22, 23), 5.47 (1H,d, J=1.8 Hz, C═CHCN), 5.78 (1H, d, J=11.1 Hz, H-7), 6.31 (1H, d, J=11.1Hz, H-6). MS m/z (%) of the mixture: 711 (M⁺, 5), 649 (18), 592 (61),565 (76), 517 (20), 408 (26), 109 (92), 75 (99), 73 (100).

Example 69 E-isomer and Z-isomer of1α-[(t-butyldimethylsilyl)oxy]-2-[2-(formyl)-ethylidene]-22-ene-25-[(methoxymethyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 141a and 141b)

To a solution of Compound 140 (59.6 mg, 0.084 mmol, 140a:140b=ca. 1:1)in dry toluene (1 mL) cooled to −78° C. was added diisobutylaluminumhydride (126 μL, 0.126 mmol, 1.0 M solution in hexane), and the mixturewas stirred for 1.5 h at the same temperature. The reaction mixture wasdiluted with hexane, and directly loaded onto silica gel column (5 g).The column was eluted with 5% AcOEt/hexane to afford Compound 141 (56.0mg, 94%) as a mixture of two stereoisomers. The ratio of the isomers141a (E-isomer) and 141b (Z-isomer)-constituting the mixture was ca.1:1.

NMR Data of the Mixture

141a: ¹H NMR (CDCl₃) δ: 0.01 -0.10 (12H, Si-Me×4), 0.57 (3H, s, H-18),0.84, 0.92 (each 9H, s, Si-tBu'2), 1.03 (3H, d, J=6.6 Hz, H-21), 1.20(6H, s, H-26, 27), 2.42 (2H, m, H-4), 2.80 (1H, m, H-9), 3.05 (1H, m,H-10), 3.37 (3H, s, OMe), 4.56 (1H, m, H-1), 4.73 (2H, s, OCH₂O), 5.35(2H, m, H-22, 23), 5.46 (1H, t, J=3.2 Hz, H-3), 5.79 (1H, d, J=11.4 Hz,H-7), 6.16 (1H, m, C═CH), 6.19 (1H, d, J=11.4 Hz, H-6), 10.18 (1H, d,J=7.9 Hz, CHO).

141b: ¹H NMR (CDCl₃) δ: 0.01 -0.10 (12H, Si-Me×4), 0.56 (3H, s, H-18),0.84, 0.93 (each 9H, s, Si-tBu×2), 1.03 (3H, d, J=6.6 Hz, H-21), 1.20(6H, s, H-26, 27), 2.65 (1H, m, H-4), 2.80 (1H, m, H-9), 3.00 (1H, m,H-10), 3.37 (3H, s, OMe), 4.70 (1H, m, H-3), 4.73 (2H, s, OCH₂O), 5.35(2H, m, H-22, 23), 5.53 (1H, m, H-1), 5.84 (1H, d, J=11.3 Hz, H-7), 6.17(1H, m, C═CH), 6.31 (1H, d, J=11.3 Hz, H-6), 10.16 (1H, d, J=7.9 Hz,CHO). MS m/z (%) of the mixture: 714 (M⁺, 9), 652 (13), 595 (20), 582(13), 520 (34), 491 (23), 463 (14), 411 (17), 109 (33), 75 (100).

Example 70 E-isomer and Z-isomer of1α-[(t-butyldimethylsilyl)oxy]-2-[2-(hydroxy)-ethylidene]-22-ene-25-[(methoxymethyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 142a and 142b)

NaBH₄ (3.6 mg, 0.094 mmol) was added to a solution of Compound 141 (56.0mg, 0.078 mmol, 141a:141b=ca. 1:1) in MeOH-THF (v/v, 2:1, 1.5 mL) cooledto 0° C. After being stirred for 1 h at 0° C., into the mixture waspoured ice water, and extracted with AcOEt. The organic layer was washedwith saturated brine, dried over anhydrous MgSO₄, and evaporated invacuo. The residue was purified by silica gel column chromatography (6g; 8% AcOEt/hexane) to give Compounds 142a (26.3 mg, E-isomer) and 142b(22.7 mg, Z-isomer). The total yield was 87%.

NMR Data of the Mixture

142a: ¹H NMR (CDCl₃) δ: 0.02, 0.06, 0.08 (3H, 3H, 6H, s, Si-Me×4), 0.56(3H, s, H-18), 0.85, 0.92 (each 9H, s, Si-tBu×2), 1.02 (3H, d, J=6.6 Hz,H-21), 1.20 (6H, s, H-26, 27), 2.30 (2H, m, H-4), 2.80 (1H, m, H-9),2.88 (1H, dd, J=12.7, 4.6 Hz, H-10), 3.37 (3H, s, OMe), 4.20, 4.30 (each1H, m, CH₂OH), 4.37 (1H, dd, J=9.5, 4.0 Hz, H-1), 4.73 (2H, s, OCH₂O),4.81 (1H, t, J=3.8 Hz, H-3), 5.33 (2H, m, H-22, 23), 5.72 (1H, m, C═CH),5.85 (1H, d, J=11.1 Hz, H-7), 6.14 (1H, d, J=11.1 Hz, H-6).

142b: ¹H NMR (CDCl₃) δ: 0.01, 0.08, 0.08, 0.09 (each 3H, s, Si-Me×4),0.55 (3H, s, H-18), 0.84, 0.93 (each 9H, s, Si-tBu×2), 1.02 (3H, d,J=6.6 Hz, H-21), 1.20 (6H, s, H-26, 27), 2.55 (1H, dd, J=12.5, 4.9 Hz,H-4), 2.83 (2H, m, H-9, 10), 3.37 (3H, s, OMe), 4.22 (1H, dd, J=12.4,7.0 Hz, CH₂OH), 4.30 (1H, dd, J=12.4, 7.0 Hz, CH₂OH), 4.48 (1H, m, H-3),4.73 (2H, s, OCH₂O), 4.86 (1H, t, J=3.2 Hz, H-1), 5.33 (2H, m, H-22,23), 5.72 (1H, dt, J=7.0, 1.3 Hz, C═CH), 5.80 (1H, d, J=11.1 Hz, H-7),6.25 (1H, d, J=11.1 Hz, H-6).

142a and 142b MS m/z (%) of the mixture: 716 (M⁺, 1), 584 (39), 522(14), 491 (9), 147 (8), 109 (19), 75 (100).

Example 711α,25-dihydroxy-2-[2-(hydroxy)-ethylidene]-22-ene-19-norvitamin D₃(E-isomer) (Compound 102a)

A mixture of Compound 142a (26.3 mg, 0.037 mmol) and camphor sulfonicacid (51.2 mg, 0.220 mmol) in dry MeOH (1 mL) was stirred at roomtemperature for 2 h. A 5% NaHCO₃ aqueous solution was added, and themixture was extracted with AcOEt. The organic phase was washed withsaturated brine, and dried over anhydrous MgSO₄. Solvents wereevaporated in vacuo, and the residue was purified by silica gel columnchromatography (5 g; 2% MeOHIAcOEt) to afford Compound 102a (15.6 mg,96%). The desired product was further purified by HPLC (YMC-Pack ODS-AMSH-342-5, 150×20 mm, 20% H₂O in MeOH) to give pure Compound 102a (12.5mg).

102a: ¹H NMR (CD₃OD) δ: 0.59 (3H, s, H-18), 1.05 (3H, d, J=6.6 Hz,H-21), 1.16 (6H, s, H-26, 27), 2.35 (1H, br, d, J=13.9 Hz, H-4), 2.43(1H, dd, J=13.9, 2.9 Hz, H-4), 2.86 (1H, m, H-9), 3.11 (1H, d, J=12.8,5.0 Hz, H-10), 4.24 (2H, m, CH₂OH), 4.30 (1H, m, H-1), 4.83 (1H, m,H-3), 5.31, 5.42 (each 1H, m, H-22, 23), 5.79 (1H, dt, J=6.9, 1.8 Hz,C═CH), 5.91 (1H, d, J=11.1 Hz, H-7), 6.23 (1H, d, J=11.1 Hz, H-6). UVλmax (EtOH): 246 (ε 37,000), 254 (ε 42,000), 263 (ε 27,800) nm. MS m/z(%): 444 (M⁺, 7), 426 (5), 408 (22), 390 (9), 372 (14), 281 (4), 263(11), 252 (100), 147 (9), 109 (12). HR-MS m/z: 444.3246 (Calcd forC₂₈H₄₄O₄: 444.3240).

Example 721α,25-dihydroxy-2-[2-(hydroxy)-ethylidene]-22-ene-19-norvitamin D₃(Z-isomer) (Compound 102b)

A mixture of Compound 142b (22.7 mg, 0.032 mmol) and camphor sulfonicacid (44.1 mg, 0.190 mmol) in dry MeOH (1 mL) was stirred at roomtemperature for 2.5 h. A 5% NaHCO₃ aqueous solution was added, and thesolution was extracted with AcOEt. The organic phase was washed withsaturated brine, and dried over anhydrous MgSO₄. Evaporation of thesolvent in vacuo gave the residue, which was purified by silica gelcolumn chromatography (5 g; 2% MeOH/AcOEt) to afford Compound 102b (13.5mg, 96%). The desired product was further purified by HPLC (YMC-PackODS-AM SH-342-5, 150×20 mm, 20% H₂O in MeOH) to give pure Compound 102b(12.6 mg).

102b: ¹H NMR (CD₃OD) δ: 0.61 (3H, s, H-18), 1.04 (3H, d, J=6.6 Hz,H-21), 1.16 (6H, s, H-26, 27), 2.65 (1H, dd, J=12.4, 5.0 Hz, H-4), 2.85(1H, m, H-9), 2.93 (1H, d, J=14.4, 3.0 Hz, H-10), 4.25 (2H, m, CH₂OH),4.39 (1H, m, H-3), 4.87 (1H, t, J=3.0 Hz, H-1), 5.31, 5.42 (each 1H, m,H-22, 23), 5.77 (1H, dt, J=6.9, 1.7 Hz, C═CH), 5.89 (1H, d, J=11.1 Hz,H-7), 6.32 (1H, d, J=11.1 Hz, H-6). UV λmax (EtOH): 246 (ε 32,500), 254(ε 37,200), 263 (ε 24,500) nm. MS m/z (%): 444 (M⁺, 10), 426 (5), 408(23), 390 (27), 372 (91), 281 (54), 263 (79), 252 (57), 147 (86), 109(100). HR-MS m/z: 444.3227 (Calcd for C₂₈H₄₄O₄: 444.3240).

Example 73 1α-[(t-butyldimethylsilyl)oxyl-2β,2′-epoxy-and1α-[(t-butyldimethylsilyl)oxy]-2α,2′-epoxy-22-ene-25-[(triethylsilyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 143a and 143b)

To a solution of A-ring phosfine oxide 13 (106.0 mg, 0.177 mmol, amixture of ca. 3:1) in dry THF (1 mL) cooled to −78° C. was added n-BuLi(112 μL, 0.177 mmol, 1.58 M solution in hexane), and the resultingsolution was stirred for 15 min. To this solution was added a solutionof C/D-ring ketone 120b (46.4 mg, 0.118 mmol) in dry THF (1.3 mL), andthe reaction mixture was warmed from −78° C. to 0° C. over 3 h, at whichpoint the reaction mixture was quenched with a saturated NH₄Cl aqueoussolution, and extracted with AcOEt. The AcOEt layer was washed withsaturated brine, dried over anhydrous MgSO₄, and evaporated in vacuo.The residue was purified by silica gel column chromatography (10 g; 2%AcOEt/hexane) to afford Compound 143 (44.4 mg, 49% based on 120b) as amixture of two stereoisomers 143a:143b=ca. 3:1 ratio, and 15% AcOEt inhexane to give the unreacted starting material 120b (22.6 mg).

NMR Data of the Mixture

143a (major product): ¹H NMR (CDCl₃) δ: 0.02-0.06 (12H, Si-Me×4), 0.56(3H, s, H-18), 0.57 (6H, q, J=7.9 Hz, Si—CH₂CH₃×3), 0.86, 0.88 (each 9H,s, Si-tBu×2), 0.95 (9H, t, J=7.9 Hz, Si—CH₂CH₃×3), 1.02 (3H, d, J=6.6Hz, H-21), 1.17 (6H, s, H-26, 27), 2.73, 2.82 (each 1H, d, J=5.5 Hz,CH₂O), 3.81, 3.87 (each 1H, m), 5.23-5.42 (2H, m), 5.82 (1H, d, J=11.0Hz, H-7), 6.21 (1H, d, J=11.0 Hz, H-6).

143b (minor product): ¹H NMR (CDCl₃) δ: 0.02-0.06 (12H, Si-Me×4), 0.56(3H, s, H-18), 0.57 (6H, q, J=7.9 Hz, Si—CH₂CH₃×3), 0.86, 0.88 (each 9H,s, Si-tBu×2), 0.95 (9H, t, J=7.9 Hz, Si—CH₂CH₃×3), 1.02 (3H, d, J=6.6Hz, H-21), 1.17 (6H, s, H-26, 27), 2.57, 2.92 (each 1H, d, J=5.5. Hz,CH₂—O), 3.68, 4.03 (each 1H, m), 5.23-5.42 (2H, m), 5.82 (1H, d, J=11.0Hz, H-7), 6.27 (1H, d, J=11.0 Hz, H-6). MS m/z (%) of the mixture: 772(M⁺, 4), 715 (10), 583 (6), 451 (3), 173 (100).

Example 74 1α,25 -dihydroxy-2β,2′-epoxy-22-ene-19-norvitamin D₃(Compound 103 a), 1α,25-dihydroxy-2α,2′-epoxy-22-ene-19-norvitamin D₃(Compound 103b),1α,2β,25-trihydroxy-2α-fluoromethyl-22-ene-19-norvitamin D₃ (Compound104a) and 1α,2α,25-trihydroxy-2β-fluoromethyl-22-ene-19-norvitamin D₃(Compound 104b)

A mixture of Compound 143 (75.1 mg, 0.097 mmol, 143a:143b=ca. 3:1) andtetrabutylammonium fluoride (0.583 mL, 0.583 mmol, 1.0 M solution inTHF) in dry THF (1 mL) was stirred at room temperature for 4 h. Themixture was poured into ice water, and extracted with AcOEt. The organicphase was washed with saturated brine, and dried over anhydrous MgSO₄.Removal of the solvent in vacuo afforded the residue, which was purifiedby silica gel column chromatography (5 g; 70% AcOEt/hexane) to yieldCompound 103 (31.1 mg, 74%) as a mixture of two stereoisomers. The ratioof the isomers 103a and 103b constituting the mixture was ca. 3:1. Thecompound 104 was not isolated.

The mixture (11 mg) of Compounds 103a and 103b was separated by HPLC(LiChrosorb Si 60, Hibar, 250×4 mm, hexane: CH₂Cl₂:methanol=50:50:6) togive compounds 103a (4.8 mg) and 103b (807 μg), respectively.

103a: ¹H NMR (CDCl₃) δ: 0.58 (3H, s, H-18), 1.04 (3H, d, J=6.6 Hz,H-21), 1.20 (6H, s, H-26, 27), 2.31 (1H, dd, J=13.5, 8.6 Hz, H-10), 2.40(1H, dd, J=13.6, 6.2 Hz, H-4), 2.61 (1H, dd, J=13.6, 3.3 Hz, H-4), 2.81(1H, m, H-9), 2.84 (1H, d, J=4.7 Hz, CH₂O), 2.94 (1H, dd, J=13.5, 4.0Hz, H-10), 3.07 (1H, d, J=4.7 Hz, CH₂O), 3.81 (1H, m, H-3), 3.98 (1H, m,H-1), 5.39 (2H, m, H-22, 23), 5.85 (1H, d, J=11.1 Hz, H-7), 6.39 (1H, d,J=11.1 Hz, H-6).

103b: ¹H NMR (CDCl₃) δ: 0.58 (3H, s, H-18), 1.05 (3H, d, J=6.6 Hz,H-21), 1.21 (6H, s, H-26, 27),2.31 (1H, dd, J=13.7, 6.2 Hz, H-10), 2.36(1H, dd, J=13.7, 8.4 Hz, H-10), 2.71 (1H, dd, J=13.7, 3.6 Hz, H-4),2.81(1H, m, H-9), 2.86 (1H, dd, J=13.7, 4.4 Hz, H-10), 2.94, 2.99 (each 1H,dd, J=4.7 Hz, CH₂O), 3.82 (1H, m, H-3), 3.90 (1H, m, H-1), 5.40 (2H, m,H-22, 23), 5.87 (1H, d, J=11.2 Hz, H-7), 6.37 (1H, d, J=11.2 Hz, H-6).

Example 75 1α,2β,25-trihydroxy-2α-methyl-22-en-19-norvitamin D₃(Compound 105a) and 1α,2α,25-trihydroxy-2β-methyl-22-en-19-norvitamin D₃(Compound 105b)

To a suspension of LiAlH₄ (1.0 mg, 0.027 mmol) in dry THF (1 mL) wasadded a solution of Compound 103 (11.7 mg, 0.027 mmol, a mixture of ca.3:1), and the reaction mixture was stirred for 3 h at room temperature.An aqueous solution of potassium sodium tartrate was added to thereaction mixture, and the mixture was extracted with AcOEt. The organicphase was washed with saturated brine, dried over anhydrous MgSO₄, anddistilled off. The residue was purified by silica gel columnchromatography (5 g, 75% AcOEt/hexane) to obtain Compound 105 as amixture of two kinds of stereoisomers (3.9 mg, 33%, 105a:105b=ca. 3:1).The mixture of Compounds 105a and 105b was separated and purified byHPLC (YMC-Pack ODS-AM SH-342-5, 150×20 mm, 25% H₂O/MeOH) to obtainCompound 105a (1.58 mg) and Compound 105b (261 μg).

105a: ¹H NMR (CDCl₃) δ: 0.56 (3H, s, H-18), 1.04 (3H, d, J=6.6 Hz,H-21), 1.20 (6H, s, H-26, 27), 1.24 (3H, s, 2-Me), 2.36 (1H, dd, J=14.5,4.6 Hz, H-4), 2.54 (1H, d, J=14.5 Hz, H-4), 2.79 (1H, m, H-9), 2.93 (1H,dd, J=12.6, 4.3 Hz, H-10), 3.73 (2H, m, H-1, 3), 5.39 (2H, m, H-22, 23),5.83 (1H, d, J=11.2 Hz, H-7), 6.29 (1H, d, J=11.2 Hz, H-6). MS m/z (%):432 (M⁺, 37), 414 (34), 396 (11), 378 (1.2), 360 (14), 305 (21), 287(37), 269 (37), 251 (21), 135 (100). HR-MS m/z: 432.3221 (Calcd forC₂₇H₄₄O₄: 432.3240). UV λmax (EtOH): 244, 252, 261 nm.

105b: ¹H NMR (CDCl₃) δ: 0.57 (3H, s, H-18), 1.04 (3H, d, J=6.6 Hz,H-21), 1.20 (6H, s, H-26, 27), 1.30 (3H, s, 2-Me), 2.49 (1H, dd, J=14.2,3.4 Hz, H-4), 2.62 (1H, dd, J=14.2, 6.5 Hz, H-4), 2.67 (1H, dd, J=13.6,4.0 Hz, H-10), 2.80 (1H, m, H-9), 3.74, 3.77 (each 1H, m, H-1, 3), 5.39(2H, m, H-22, 23), 5.81 (1H, d, J=11.2 Hz, H-7), 6.33 (1H, d, J=11.2 Hz,H-6). MS m/z (%): 432 (M⁺, 66), 414 (31), 396 (17), 378 (20), 360 (35),305 (29), 287 (49), 269 (48), 251 (43), 135 (100). HR-MS m/z: 432.3246(Calcd for C₂₇H₄₄O₄: 432.3240). UV λmax (EtOH): 244, 252, 261 nm.

Example 7620-epi-1α-[(t-butyldimethylsilyl)oxy]-2α-[(trimethylsilyl)oxy]- and20-epi-1α-[(t-butyldimethylsilyl)oxy]-2β-[(trimethylsilyl)oxy]-22-oxa-25-[(triethylsilyl)oxy]-19-norvitamin D₃ t-butyldimethylsilyl ether(Compounds 144a, 144b)

To a solution cooled to −78° C. of A-ring phosphine oxide 22 (212.0 mg,0.321 mmol, a mixture of ca. 2:1) in dry THF (3 mL) was added n-BuLi(206 μL, 0.321 mmol, 1.56 M solution in hexane), and the resultingsolution was stirred for 15 min. To this solution was added slowly asolution of C/D-ring ketone 121 (85.0 mg, 0.214 mmol) in dry THF (1 mL),and the mixture was stirred for 2 h at −78° C., saturated NH₄Cl aqueoussolution was added to the mixture, and the mixture was extracted withAcOEt. The organic phase was washed with saturated brine, dried overanhydrous MgSO₄, and distilled off. The residue was purified by silicagel column chromatography (10 g) using 2% AcOEt/hexane to affordCompound 144 (158.8 mg, 88%) as a mixture of two kinds of stereoisomers.The ratio of the isomer 144a to the isomer 144b was ca. 3:2. Further,the unreacted starting material 121 (5.1 mg) was collected using 5%AcOEt/hexane.

NMR Data of the Mixture

144a (major product): ¹H NMR (CDCl₃) δ: 0.04-0.06 (12H, Si-Me×4), 0.13(9H, s, Si-Me×3), 0.56 (3H, s, H-18), 0.57 (6H, q, J=7.9 Hz, SiCH₂×3),0.87, 0.88 (each 9H, s, Si-tBu×2), 0.94 (9 t, J=7.9 Hz, SiCH₂CH₃×3),1.08 (3H, d, J=5.9 Hz, H-21), 1.21, 1.23 (each 3H, s, H-26, 27), 2.80(1H, m, H-9), 3.26 (1H, m, H-20), 3.32, 3.69 (each 1H, m, H-23), 3.53(1H, m, H-2), 3.80 (1H, m, H-3), 3.89 (1H, m, H-1), 5.79 (1H, d, J=11.1Hz, H-7), 6.11 (1H, d, J=11.1 Hz, H-6).

144b (minor product): ¹H NMR (CDCl₃) δ: 0.04-0.06 (12H, Si-Me×4), 0.12(9H, s, Si-Me×3), 0.54 (3H, s, H-18), 0.57 (6H, q, J=7.9 Hz, SiCH₂×3),0.86, 0.89 (each 9H, s, Si-Btu×2), 0.94 (9H, t, J=7.9 Hz, SiCH₂CH₃×3),1.08 (3H, d, J=5.9 Hz, H-21), 1.21, 1.23 (each 3 H, s, H-26, 27), 2.80(1H, m, H-9), 3.26 (1H, m, H-20), 3.32, 3.69 (each 1H, m, H-23), 3.59(1H, m, H-2), 3.80 (1H, m, H-3), 3.93 (1H, m, H-1), 5.77 (1H, d, J=11.2Hz, H-7), 6.14 (1H, d, J=11.2 Hz, H-6). MS m/z (%) of the mixture: noM⁺, 704 (10), 647 (3), 618 (7), 572 (19), 486 (20), 469 (13), 383 (17),309 (19), 75 (100).

Example 77 20-epi-1α-[(t-butyldimethylsilyl)oxy]-2α,25-dihydroxy- and20-epi-1α-[(t-butyldimethylsilyl)oxy]-2β,25-dihydroxy-22-oxa-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 145a, 145b)

A Compound 144 (153.0 mg, 0.183 mmol, a mixture of ca. 3:2) wasdissolved in THF/AcOH/H₂O (8:8:1, 4.25 mL), a solution was stirred atroom temperature for 16 h, and diluted with AcOEt. The organic phase wassuccessively washed with 5% NaHCO₃ and saturated brine, and dried overanhydrous Na₂SO₄, and distilled off. The residue was purified by silicagel column chromatography (6 g) using 5% AcOEt/hexane to afford Compound146 (37.0 mg, 27%) as a mixture of two kinds of stereoisomers, and using10% AcOEt/hexane to afford Compound 145 (77.1 mg, 65%) as a mixture oftwo kinds of stereoisomers. The ratio of the isomer 145a to the isomer145b and the ratio of the isomer 146a to the isomer 146b was ca. 3:2,respectively.

NMR Data of the Mixture

145a (major product): ¹H NMR (CDCl₃) δ: 0.06-0.10 (12H, Si-Me×4), 0.56(3H, s, H-18), 0.87, 0.88 (each 9H, s, Si-tBu×2), 1.14 (3H, d, J=5.9 Hz,H-21), 1.22, 1.24 (each 3H, s, H-26, 27), 2.80 (1H, m, H-9), 3.28 (1H,m, H-20), 3.46, 3.85 (each 1H, m, H-23), 3.51 (1H, m, H-2), 3.59 (1H, s,OH), 3.92 (1H, m, H-3), 4.00 (1H, m, H-1), 5.78 (1H, d, J=11.1 Hz, H-7),6.16 (1H, d, J=11.1 Hz, H-6).

145b (minor product): ¹H NMR (CDCl₃) δ: 0.06-0.10 (12H, Si-Me×4), 0.54(3H, s, H-18), 0.86, 0.89 (each 9H, s, Si-tBu×2), 1.14 (3H, d, J=5.9 Hz,H-21), 1.23, 1.24 (each 3H, s, H-26, 27), 2.80 (1H, m, H-9), 3.28 (1H,m, H-20), 3.46, 3.85 (each 1H, m, H-23), 3.59 (1H, m, H-2), 3.59 (1H, s,OH), 4.00 (2H, m, H-3, 1), 5.78 (1H, d, J=11.2 Hz, H-7), 6.19 (1H, d,J=11.2 Hz, H-6). MS m/z (%) of the mixture: 650 (M⁺, 2), 632 (8), 546(6), 489 (8), 443 (10), 357 (8), 265 (22), 113 (30), 75 (100).

NMR Data of the Mixture

146a (major product): ¹H NMR (CDCl₃) δ: 0.06-0.10 (12H, Si-Me×4), 0.56(3H, s, H-18), 0.56 (6H, q, J=7.9 Hz, SiCH₂×3), 0.87, 0.88 (each 9H, s,Si-tBu×2), 0.94 (9H, t, J=7.9 Hz, SiCH₂CH₃×3), 1.09 (3H, d, J=5.9 Hz,H-21), 1.21, 1.23 (each 3H, s, H-26, 27), 2.81 (1H, m, H-9), 3.26 (1H,m, H-20), 3.32, 3.70 (each 1H, m, H-23), 3.51 (1H, m, H-2), 3.91 (1H, m,H-3), 4.01 (1H, m, H-1), 5.78 (1H, d, J=11.1 Hz, H-7), 6.17 (1H, d,J=11.1 Hz, H-6).

146b (minor product): ¹H NMR (CDCl₃) δ: 0.06-0.10 (12H, Si-Me×4), 0.55(3H, s, H-18), 0.56 (6H, q, J=7.9 Hz, SiCH₂×3), 0.86, 0.89 (each 9H, s,Si-tBu×2), 0.94 (9H, t, J=7.9 Hz, SiCH₂CH₃×3), 1.09 (3H, d, J=5.9 Hz,H-21), 1.21, 1.23 (each 3H, s, H-26, 27), 2.81 (1H, m, H-9), 3.26 (1H,m, H-20), 3.32, 3.70 (each 1H, m, H-23), 3.59 (1H, m, H-2), 4.01 (2H, m,H-1, 3), 5.78 (1H, d, J=11.2 Hz, H-7), 6.20 (1H, d, J=11.2 Hz, H-6). MSm/z (%) of the mixture: 764 (M⁺, 1), 707 (1), 632 (4), 575 (2), 546 (3),489 (4), 443 (5), 357 (20), 265 (11), 103 (31), 75 (100).

Example 7820-epi-1α-[(t-butyldimethylsilyl)oxy]-2α-[2-(t-butyldimethylsilyl)oxy]-ethoxy]-and20-epi-1α-[(t-butyldimethylsilyl)oxy]-2β-[2-(t-butyldimethylsilyl)oxy)-ethoxy]-22-oxa-25-hydroxy-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 147a, 147b)

To a solution cooled to 0° C. of Compound 145 (73.5 mg, 0.113 mmol, amixture of ca. 3:2) in dry DMF (2 mL) were added NaH (135.0 mg, 3.375mmol, 60% paraffin liquid) and (2-bromoethoxy)-tert-butyldimethylsilane(118 μl, 0.550 mmol), and the resulting solution was stirred vigorously.After 19 h, the reaction mixture was poured into ice water, and thenextracted with AcOEt/hexane (1:1). The organic phase was washed withsaturated brine, dried over anhydrous MgSO₄, and distilled off. Theresidue was purified by silica gel column chromatography (10 g, 10-15%AcOEt/hexane) to afford Compound 147 (65.0 mg, 71%) as a mixture of twokinds of stereoisomers. The ratio of the isomer 147a to the isomer 147bwas ca. 3:2.

147: ¹H NMR (CDCl₃) δ: 0.05-0.07 (18H, Si-Me×6), 0.54, 0.55 (ca. 2:3)(3H, s, H-18), 0.86-0.89 (27H, Si-tBu×3), 1.13 (3H, d, J=5.5 Hz, H-21),1.23, 1.24 (each 3H, s, H-26, 27), 2.80 (1H, m, H-9), 3.2-4.1 (10H, m,OCH₂CH₂O, H-1, 2, 3, 20, 23), 5.77 (1H, H-7), 6.14 (1H, H-6). MS m/z(%): no M⁺, 790 (1), 676 (4), 658 (5), 572 (6), 526 (5), 397 (18), 233(74), 75 (100).

Example 79 20-epi-1α,25-dihydroxy-2α-(2-hydroxyethoxy)- and20-epi-1α,25-dihydroxy-2β-(2-hydroxyethoxy)-22-oxa-19-norvitamin D₃(Compounds 106a, 106b)

To a solution of Compound 147 (63.0 mg, 0.0778 mmol) in dry MeOH (1.5mL) was added camphor sulfonic acid (108.5 mg, 0.467 mmol), and theresulting solution was stirred at room temperature for 2 h. The reactionmixture was poured into 5% NaHCO₃, and extracted with AcOEt. The organicphase was washed with saturated brine, dried over anhydrous MgSO₄, anddistilled off. The residue was purified by silica gel columnchromatography (5 g, 2% MeOH/AcOEt) to obtain a mixture of Compounds106a and 106b (33.0 mg, 91%, ca. 3:2 ratio). The mixture of Compounds106a and 106b was separated and purified by HPLC (YMC-Pack ODS-AMSH-342-5, 150×20 mm, 25% H₂O/MeOH) to obtain Compound 106a (13.9 mg) andCompound 106b (10.3 mg).

106a: ¹H NMR (CDCl₃) δ: 0.55 (3H, s, H-18), 1.12 (3H, d, J=5.9 Hz,H-21), 1.22, 1.23 (each 3H, s, H-26, 27), 2.60 (1H, dd, J=13.4, 4.5 Hz,H-4), 2.79 (1H, m, H-9), 2.86 (1H, dd, J=14.5, 4.8 Hz, H-10), 3.26 (1H,m, H-20), 3.31 (1H, dd, J=8.1, 2.7 Hz, H-2), 3.45 (1H, m, H-23), 3.57(1H, s, OH), 3.66-3.86 (5H, m, OCH₂CH₂O, H-23), 3.92 (1H, m, H-3), 4.14(1H, m, H-1), 5.79 (1H, d, J=11.2 Hz, H-7), 6.33 (1H, d, J=11.2 Hz,H-6). UV λmax (EtOH): 243 (ε 29,600), 251 (ε 34,500), 261 (ε 23,200) nm.MS m/z (%): 466 (M⁺, 39), 448 (30), 430 (13), 362 (14), 345 (12), 317(13), 237 (9), 133 (20), 113 (50), 69 (100). HR-MS m/z: 466.3267 (Calcdfor C₂₇H₄₆O₆: 466.3294).

106b: ¹H NMR (CDCl₃) δ: 0.55 (3H, s, H-18), 1.13 (3H, d, J=5.9 Hz,H-21), 1.22, 1.24 (each 3H, s, H-26, 27), 2.34 (1H, br. d, J=14.1 Hz,H-4), 2.48 (1H, dm, J=14.1 Hz, H-4), 2.67 (1H, br. s, OH), 2.79 (1H, m,H-9), 3.07 (1H, dd, J=13.4, 3.8 Hz, H-10), 3.27.(2H, m, H-2, 20), 3.45(1H, m, H-23), 3.56 (1H, s, OH), 3.64-3.87 (6H, m, OCH₂CH₂O, H-1, 23),4.17 (1H, m, H-3), 5.82 (1H, d, J=11.2 Hz, H-7), 6.27 (1H, d, J=11.2 Hz,H-6). UV λmax (EtOH): 243 (ε 32,500), 251 (ε 37,900), 261 (ε 25,100) nm.MS m/z (%): 466 (M⁺, 28), 448 (22), 430 (11), 362 (9), 345 (9), 317 (9),237 (11), 133 (19), 113 (43), 69 (100). HR-MS m/z: 466.3300 (Calcd forC₂₇H₄₆O₆: 466.3294).

Example 8020-epi-1α-[(t-butyldimethylsilyl)oxy]-2-oxo-22-oxa-25-[(triethylsilyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether (Compound 148)

To a solution cooled to −78° C. of oxalyl chloride (8.3 μL, 0.095 mmol)in dry CH₂Cl₂ (1 mL) was added a solution of DMSO (13.5 μL, 0.190 mmol)in dry CH₂Cl₂ (0.2 mL). After being stirred for 5 min, to this mixturewas added a solution of Compound 146 (60.7 mg, 0.079 mmol, a mixture ofca. 3:2) in dry CH₂Cl₂ (1.2 mL). The reaction mixture was stirred for 15min at −78° C., and Et₃N (55 μL, 0.397 mmol) was added: The wholemixture was stirred at −78° C. for 30 min and at 0° C. for 10 min,quenched with ice water, and extracted with CH₂Cl₂. The organic phasewas washed with saturated brine, dried over anhydrous MgSO₄, anddistilled off. The residue was purified by silica gel columnchromatography (5 g, 2% AcOEt/hexane) to afford Compound 148 (59.5 mg,98%) as a single compound.

148: ¹H NMR (CDCl₃) δ: 0.057, 0.066, 0.070, 0.097 (each 3H, s, Si-Me×4),0.56 (3H, s, H-18), 0.57 (6H, q, J=7.9 Hz, SiCH₂×3), 0.87, 0.89 (each9H, s, Si-tBu×2), 0.94 (9H, t, =7.9 Hz, SiCH₂CH₃×3), 1.09 (3H, d, J=5.9Hz, H-21), 1.21, 1.23 (each 3H, s, H-26, 27), 2.45 (1H, dd, J=13.2, 8.7Hz), 2.52 (1H, dd, J=14.0, 4.0 Hz), 2.70 (2H, m), 2.81 (1H, m, H-9),3.26 (1H, m, H-20), 3.32, 3.70 (each 1H, m, H-23), 4.36 (1H, dd, J=6.3,4.2 Hz), 4.55 (1H, dd, J=8.7, 5.5 Hz), 5.79 (1H, d, J=11.0 Hz, H-7),6.37 (1H, d, J=11.0 Hz, H-6). MS m/z (%): no M⁺, 705 (8), 573 (12), 487(22), 355 (12), 103 (51), 75 (100).

Example 81 E-isomer and Z-isomer of20-epi-1α-[(t-butyldimethylsilyl)oxy]-2-cyanomethylene-22-oxa-25-[(triethylsilyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 149a and 149b)

To a solution cooled to −40° C. of diethyl (cyanomethyl)phosphonate (51μL, 0.315 mmol) in dry THF (1 mL) was added n-BuLi (202 μL, 0.315 mmol,1.56 M solution in hexane). The mixture was stirred for 15 min, and asolution of Compound 148 (120.3 mg, 0.157 mmol) in dry THF (1.2 mL) wasadded slowly. The reaction mixture was stirred at −40.° C. for 1.5 h,saturated NH₄Cl aqueous solution was added to the mixture, and themixture was extracted with AcOEt. The organic phase was washed withsaturated brine, dried over anhydrous MgSO₄, and distilled off. Theresidue was purified by silica gel column chromatography (8 g, 1%AcOEt/hexane) to afford Compound 149 (120.6 mg, 97%) as a mixture of twokinds of stereoisomers. The ratio of the isomer 149a (E-isomer) to theisomer 149b (Z-isomer) was ca. 1:1.

NMR Data of the Mixture

149a: ¹H NMR (CDCl₃) δ: 0.05, 0.07, 0.10, 0.12 (each 3H, s, Si-Me×4),0.56 (3H, s, H-18), 0.56 (6H, q, J=7.9 Hz, SiCH₂×3), 0.84, 0.92 (each9H, s, 2×Si-tBu×2), 0.93 (9H, t, J=7.9 Hz, SiCH₂CH₃×3), 1.09 (3H, d,J=5.9 Hz, H-21), 1.21, 1.23 (each 3H, s, H-26, 27), 2.31, 2.37 (each 1H,m, H-4), 2.80 (1H, m, H-9), 3.12 (1H, m, H-10), 3.26 (1H, m, H-20),3.32, 3.69 (each 1H, m, H-23), 4.46 (1H, m, H-1), 4.99 (1H, t, J=2.8 Hz,H-3), 5.47 (1H, d, J=1.8 Hz, C═CHCN), 5.80 (1H, d, J=11.1 Hz, H-7), 6.20(1H, d, J=11.1 Hz, H-6).

149b: ¹H NMR (CDCl₃) δ: 0.06, 0.08, 0.11, 0.13 (each 3H, s, Si-Me×4),0.56 (3H, s, H-18), 0.56 (6H, q, J=7.9 Hz, SiCH₂×3), 0.84, 0.92 (each9H, s, 2×Si-tBu), 0.94 (9H, t, J=7.9 Hz, SiCH₂CH₃×3), 1.09 (3H, d, J=5.9Hz, H-21), 1.21, 1.23 (each 3H, s, H-26, 27), 2.61 (1H, m, H-4), 2.82(1H, m, H-9), 2.99 (1H, m, H-10), 3.26 (1H, m, H-20), 3.32, 3.70 (each1H, m, H-23), 4.58 (1H, ddd, J=1.0, 5.9, 1.9 Hz, H-3), 5.04 (1H, t,J=2.7 Hz, H-1), 5.47 (1H, d, J=1.9 Hz, C═CHCN), 5.77 (1H, d, J=11.2 Hz,H-7), 6.33 (1H, d, J=11.2 Hz, H-6). MS m/z (%) of the mixture: 785 (M⁺,2), 728 (8), 701 (12), 653 (6), 596 (9), 569 (16), 510 (17), 483 (11),103 (66), 75 (100).

Example 82 E-isomer and Z-isomer of20-epi-1α-[(t-butyldimethylsilyl)oxy]-2-[2-(formyl)-ethylidene]-22-oxa-25-[(triethylsilyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 150a and 150b)

To a solution cooled to −78° C. of Compound 149 (77.0 m., 0.098 mmol, amixture of ca. 1:1) in dry toluene (1 mL) was added diisobutylaluminumhydride (147 μL, 0.147 mmol, 1.0 M solution in toluene), and the mixturewas stirred for 2 h. The reaction mixture was diluted with hexane, anddirectly purified by silica gel column chromatography (8 g, 5%AcOEt/hexane) to afford Compound 150 (66.9 mg, 87%) as a mixture of twokinds of stereoisomers. The ratio of the isomer 150a (E-isomer) to theisomer 150b (Z-isomer) was ca. 1:1.

NMR Data of the Mixture

150a: ¹H NMR (CDCl₃) δ: 0.01, 0.07, 0.09, 0.10 (each 3H, s, Si-Me×4),0.57 (3H, s, H-18), 0.56 (6H, q, J=7.9 Hz, SiCH₂×3), 0.84, 0.92 (each9H, s, Si-tBu×2), 0.94 (9H, t, J=7.9 Hz, SiCH₂CH₃×3), 1.09 (3H, d, J=5.9Hz, H-21), 1.21, 1.23 (each 3H, s, H-26, 27), 2.42 (2H, m, H-4), 2.80(1H, m, H-9), 3.05 (1H, dd, J=12.8, 5.3 Hz, H-10), 3.26 (1H, m, H20),3.32, 3.69 (each 1H, m, H-23), 4.57 (1H, m, H-1), 5.46 (1H, t, J=3.3 Hz,H-3), 5.83 (1H, d, J=11.1 Hz, H-7), 6.15 (1H, dd, J=7.9, 1.1 Hz, C═CH),6.19 (1H, d, J=11.1 Hz, H-6), 10.18 (1H, d, J=7.9 Hz, CHO).

150b: ¹H NMR (CDCl₃) δ: 0.02, 0.08, 0.10, 0.11 (each 3H, s, Si-Me×4),0.56 (3H, s, H-18), 0.57 (6H, q, J=7.9. Hz, SiCH₂×3), 0.84, 0.93 (each9H, s, Si-tBu×2), 0.94 (9H, t, J=7.9 Hz, SiCH₂CH₃×3), 1.09 (3H, d, J=5.9Hz, H-21), 1.21, 1.23 (each 3H, s, H-26, 27), 2.65 (1H, m, H-4), 2.80(1H, m, H-9), 3.00 (1H, m, H-10), 3.26 (1H, m, H-20), 3.32, 3.71 (each1H, m, H-23), 4.69 (1H, m, H-3), 5.54 (1H, m, H-1), 5.78 (1H, d, J=11.2Hz, H-7), 6.16 (1H, dd, J=7.9, 1.1 Hz, C═CH), 6.32 (1H, d, J=11.1 Hz,H-6), 10.16 (1H, d, J=7.9 Hz, CHO). MS m/z (%) of the mixture: 788 (M⁺,5), 731 (5), 656 (8), 627 (7), 599 (4), 524 (5), 495 (3), 409 (5), 103(42), 75 (100).

Example 83 E-isomer and Z-isomer of20-epi-1α-[(t-butyldimethylsilyl)oxy]-2-[2-(hydroxy)-ethylidene]-22-oxa-25-[(triethylsilyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 151a and 151b)

NaBH₄ (5.6 mg, 0.148 mmol) was added to a solution cooled to 0° C. ofCompound 150 (97.0 mg, 0.123 mmol, a mixture of ca. 1:1) in MeOH/THF(2:1, 1.5 mL), and the mixture was stirred for 0.5 h. The mixture waspoured into ice water, and extracted with AcOEt. The organic phase waswashed with saturated brine, dried over anhydrous MgSO₄, and distilledoff. The residue was purified by silica gel column chromatography (10 g,7% AcOEt/hexane) to obtain Compounds 151a (43.6 mg, E-isomer) and 151b(35.5 mg, Z-isomer). The total yield was 81%.

NMR Data of the Mixture

151a: ¹H NMR (CDCl₃) δ: 0.01, 0.07, 0.08 (3H, 3H, 6H, s, Si-Me'4), 0.56(3H, s, H-18), 0.56 (6H, q, J=7.9 Hz, SiCH₂×3), 0.85, 0.92 (each 9H, s,Si-tBu×2), 0.94 (9H, t, J=7.9 Hz, SiCH₂CH₃×3), 1.09 (3H, d, J=5.9 Hz,H-21), 1.21, 1.23 (each 3H, s, H-26, 27), 2.31 (2H, m, H-4), 2.80 (1H,m, H-9), 2.88 (1H, dd, J=12.6, 4.6 Hz, H-10), 3.26 (1H, m, H-20), 3.32,3.70 (each 1H, m, H-23), 4.18, 4.31 (each 1H, m, CH₂OH), 4:37 (1H, m,H-1), 4.82 (1H, t, J=3.8 Hz, H-3), 5.72 (1H, m, C═CH), 5.83 (1H, d,J=11.0 Hz, H-7), 6.15 (1H, d, J=11.0 Hz, H-6).

151b: ¹H NMR (CDCl₃) δ: 0.01, 0.07, 0.08, 0.10 (each 3H, s, Si-Me×4),0.56 (3H, s, H-18), 0.57 (6H, q, J=7.9 Hz, SiCH₂×3), 0.84, 0.93 (each9H, s, Si-tBu×2), 0.94 (9H, t, J=7.9 Hz, SiCH₂CH₃×3), 1.09 (3H, d, J=5.9Hz, H-21), 1.21, 1.23 (each 3H, s, H-26, 27), 2.55 (1H, dd, J=12.5, 5.0Hz, H-4), 2.83 (2H, m, H-9, 10), 3.26 (1H, m, H-20), 3.32, 3.70 (each1H, m, H-23), 4.22, 4.27 (each 1H, m, CH₂OH), 4.48 (1H, m, H-3), 4.86(1H, t, J=3.1 Hz, H-1), 5.72 (1H, dt, J=7.0, 1.4 Hz, C═CH), 5.79 (1H, d,J=11.1 Hz, H-7), 6.26 (1H, d, J=11.1 Hz, H-6). MS m/z (%) of themixture: 790 (M⁺, 1), 772 (1), 733 (1), 658 (45), 627 (11), 526 (7), 508(7), 376 (5), 103 (33), 75 (100).

Example 8420-epi-1α,25-dihydroxy-2-[2-(hydroxy)-ethylidene]-22-oxa-19-norvitaminD₃ (E-isomer) (Compound 107a)

To a solution of Compound 151a (43.6 mg, 0.055 mmol) in dry MeOH (1 mL)was added camphor sulfonic acid (76.8 mg, 0.331 mmol), and stirred atroom temperature for 2 h. 5% NaHCO₃ was added to the solution, and thesolution was extracted with AcOEt. The organic phase was washed withsaturated brine, dried over anhydrous MgSO₄, and distilled off. Theresidue was purified by silica gel column chromatography (5 g, 2%MeOH/AcOEt) to afford Compound 107a (23.7 mg, 96%). The desired productwas further purified by HPLC (YMC-Pack ODS-AM SH-342-5, 150×20 mm, 20%H₂O/MeOH) to obtain pure Compound 107a (20.1 mg).

107a: ¹H NMR (CDCl₃) δ: 0.54 (3H, s, H-18), 1.13 (3H, d, J=5.9 Hz,H-21), 1.22, 1.23 (each 3H, s, H-26, 27), 2.33, 2.43 (each 1H, m, H-4),2.79 (1H, m, H-9), 3.12 (1H, d, J=12.5, 4.4 Hz, H-10), 3.26 (1H, m,H-20), 3.44 (1H, m, H-23), 3.51, 3.58, 3.90 (each 1H, br. s, OH×3), 3.84(1H, dt, J=9.4, 4.3 Hz, H-23), 4.08 (1H, dd, J=12.4, 5.2 Hz, CH₂OH),4.33 (2H, m, H-1, CH₂OH), 4.79 (1H, m, H-3), 5.74 (1H, m, C═CH), 5.84(1H, d, J=11.1 Hz, H-7), 6.26 (1H, d, J=11.1 Hz, H-6). UV λmax (EtOH):246 (ε 34,600), 254 (ε 39,700), 263 (ε 26,500) nm. MS m/z (%): 448 (M⁺,9), 430 (8), 412 (14), 394 (26), 376 (12),308 (13), 263 (12), 131 (20),113 (39), 69 (100). HR-MS m/z: 448.3188 (Calcd for C₂₇H₄₄O₅: 448.3189).

Example 8520-epi-1α,25-dihydroxy-2-[2-(hydroxy)-ethylidene]-22-oxa-19-norvitaminD₃ (Z-isomer) (Compound 107b)

To a solution of Compound 151b (35.5 mg, 0.045 mmol) in dry MeOH (1 mL)was added camphor sulfonic acid (62.5 mg, 0.269 mmol), and stirred atroom temperature for 2 h. 5% NaHCO₃ was added to the solution, and thesolution was extracted with AcOEt. The organic phase was washed withsaturated brine, dried over anhydrous MgSO4, and evaporated in vacuo.The residue was purified by silica gel column chromatography (5 g, 2%MeOH/AcOEt) to afford Compound 107b (19.3 mg, 96%). The desired productwas further purified by HPLC (YMC-Pack ODS-AM SH-342-5, 150×20 mm, 20%H₂O/MeOH) to obtain pure Compound 107b (17.6 mg).

107b: ¹H NMR (CDCl₃) δ: 0.57 (3H, s, H-18), 1.13 (3H, d, J=5.9 Hz,H-21), 1.23, 1.24 (each 3H, s, H-26, 27), 2.68 (1H, dd, J=12.6, 4.5 Hz,H-4), 2.81 (1H, m, H-9), 2.88 (1H, d, J=14.2, 3.5 Hz, H-10), 3.28 (1H,m, H-20), 3.45, 3.84 (each 1H, m, H-23), 3.61 (1H, s, OH), 4.14 (1H, dd,J=12.5, 5.6 Hz, CH₂OH), 4.34 (1H, dd, J=12.5, 8.4 Hz, CH₂OH), 4.4 (1H,m, H-3), 4.84 (1H, m, H-1), 5.75 (1H, m, C═CH), 5.82 (1H, d, J=11.1 Hz,H-7), 6.38 (1H, d, J=11.1 Hz, H-6). UV λmax (EtOH): 246 (ε 32,300), 254(ε 37,100), 263 (ε 24,600) nm. MS m/z (%): 448 (M⁺, 7), 430 (7), 412(14), 394 (25), 376 (12), 308 (13), 263 (12), 131 (21), 113 (39), 69(100). HR-MS m/z: 448.3214 (Calcd for C₂₇H₄₄O₅: 448.3189).

Example 86 20-epi-1α-[(t-butyldimethylsilyl)oxy]-2β,2′-epoxy- and1α-[(t-butyldimethyisilyl)oxy]-2α,2′-epoxy-22-oxa-25-[(triethylsilyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 152a and 152b)

To a solution cooled to −78° C. of A-ring phosphine oxide 13 (104.1 mg,0.174 mmol, a mixture of ca. 3: 1) in dry THF (1 mL) was added n-BuLi(110.1 μL, 0.174 mmol, 1.58 M solution in hexane), and the resultingsolution was stirred for 15 min. To this solution was added dropwise asolution of 22-oxa Grundmann's ketone 121 (43.6 mg, 0.110 mmol) in dryTHF (1.3 mL). The mixture was stirred for 2 h with warming graduallyfrom −78° C. to 0° C., saturated NH₄Cl aqueous solution was added to themixture, and the mixture was extracted with AcOEt. The organic phase waswashed with saturated brine, dried over anhydrous MgSO₄, and distilledoff. The residue was purified by silica gel column chromatography (10 g,2% AcOEt/hexane) to afford Compound 152 (49.8 mg, 58%) as a mixture oftwo kinds of stereoisomers. The ratio of the isomer 152a to the isomer152b was ca. 5:1: Further, the unreacted starting material 121 (9.4 mg)was collected using 15% AcOEt/hexane.

N NMR Data of the Mixture

152a (major product): ¹H NMR (CDCl₃) δ: 0.03-0.08 (12H, Si-Me×4), 0.56(3H, s, H-18), 0.57 (6H, q, J=7.9 Hz, SiCH₂×3), 0.86, 0.88 (each 9H, s,Si-tBu×2), 0.94 (9H, t, J=7.9 Hz, SiCH₂CH₃×3), 1.09 (3H, d, J=5.9 Hz,H-21), 1.21, 1.23 (each 3H, s, H-26, 27), 2.73, 2.82 (each 1H, d, J=5.6Hz, OCH₂), 3.25, 3.32 (each 1H, m, H-20, 23), 3.71 (1H, m, H-23), 3.82,3.86 (each 1H, m, H-1, 3), 5.80 (1H, d, J=11.2 Hz, H-7), 6.22 (1H, d,J=11.2 Hz, H-6).

152b (minor product): ¹H NMR (CDCl₃) δ: 0.03-0.08 (12H, Si-Me×4), 0.56(3H, s, H-18), 0.57 (6H, q, J=7.9 Hz, SiCH₂×3), 0.86, 0.88 (each 9H, s,Si-tBu×2), 0.94 (9H, t, J=7.9 Hz, SiCH₂CH₃×3), 1.09 (3H, d, J=5.9 Hz,H-21), 1.21, 1.23 (each 3H, s, H-26, 27), 2.57, 2.92 (each 1H, d, J=5.5Hz, OCH₂), 3.25, 3.32 (each 1H, m, H-20, 23), 3.71 (1H, m), 3.82 (1H,m), 4.04 (1H, m), 5.82 (1H, d, J=11.0 Hz, H-7), 6.28 (1H, d, J=11.0 Hz,H-6).

Example 87 20-epi-1α,25-dihydroxy-2β,2′-epoxy-22-oxa-19-norvitamin D₃(Compound 108a), 20-epi-1α,25-dihydroxy-2α,2′-epoxy-22-oxa-19-norvitaminD₃ (Compound 108b),20-epi-1α,2β,25-trihydroxy-2α-fluoromethyl-22-oxa-19-norvitamin D₃(Compound 109a), and20-epi-1α,2α,25-trihydroxy-2β-fluoromethyl-22-oxa-19-norvitamin D₃(Compound 109a)

To a solution of Compound 152 (49.8 mg, 0.064 mmol, a mixture of ca.5:1) in dry THF (1 mL) was added tetrabutylammonium fluoride (0.385 mL,0.385 mmol, 1 M solution in THF), and the mixture was stirred at roomtemperature for 4 h. The mixture was poured into ice water, andextracted with AcOEt. The organic phase was washed with saturated brine,dried over anhydrous MgSO₄, and distilled off. The residue was purifiedby silica gel column chromatography (5 g) using 60% AcOEt/hexane toyield Compound 109 as a mixture of two kinds of stereoisomers (1.6 mg,5%, 109a:109b=ca. 5:1 ratio), and using 70% AcOEt/hexane to affordCompound 108 as a mixture of two kinds of stereoisomers (23.0 mg, 83%,108a:108b=ca. 5:1). The mixture of Compounds 108a and 108b was separatedand purified by HPLC (LiChrosorb Si 60, RT 250-4, 250×10 mm,hexane:CH₂Cl₂:2-propanol=50:50:6) to obtain Compounds 108a (9.46 mg) and108b (995 μg), respectively. The mixture of Compounds 109a and 109b wasseparated and purified by HPLC (YMC-Pack ODS-AM SH-342-5, 150×20.mm, 25%H₂O/MeOH) to-obtain Compounds 109a (813 μg) and 109b (170 μg),respectively.

108a: ¹H NMR (CDCl₃) δ: 0.56 (3H, s, H-18), 1.13 (3H, d, J=5.9 Hz,H-21), 1.22, 1.24 (each 3H, s, H-26, 27), 2.29 (1H, dd, J=13.5, 8.6 Hz,H-10), 2.40 (1H, dd, J=13.7, 6.2 Hz, H-4), 2.60 (1H, dd, J=13.7, 3.5 Hz,H-4), 2.8 (1H, m, H-9), 2.83 (1H, d, J=4.8 Hz, CH₂O), 2.94 (1H, dd,J=13.5, 4.3 Hz, H-10), 3.07 (1H, d, J=4.8 Hz, CH₂O), 3.27 (1H, m), 3.45(1H, m), 3.82 (2H, m), 3.98 (1H, dd, J=8.6, 4.2 Hz), 5.83 (1H, d, J=11.1Hz, H-7), 6.39 (1H, d, J=11.1 Hz, H-6). UV λmax (EtOH): 243, 251, 261nm.

108b: ¹H NMR (CDCl₃) δ: 0.56 (3H, s, H-18), 1.14 (3H, d, J=5.9 Hz,H-21), 1.23, 1.24 (each 3H, s, H-26, 27), 2.31 (1H, dd, J=13.7, 6.0 Hz,H-4), 2.36 (1H, dd, J=13.6, 8.7 Hz, H-10), 2.72 (1H, dd, J=13.7, 3.6 Hz,H-4), 2.81 (1H, m, H-9), 2.85 (1H, dd, J=13.6, 4.2 Hz, H-10), 2.94, 2.98(each 1H, d, J=4.7 Hz, CH₂O), 3.27 (1H, m), 3.46 (1H, m), 3.80-3.95 (3H,m), 5.85 (1H, d, J=11.2 Hz, H-7), 6.38 (1H, d, J=11.2 Hz, H-6). UV λmax(EtOH): 243, 251, 261 nm.

109a: ¹H NMR (CDCl₃) δ: 0.54 (3H, s, H-18), 1.13 (3H, d, J=5.9 Hz,H-21), 1.23, 1.24 (each 3H, s, H-26, 27), 2.48 (2H, m, H-4), 2.55 (1H,dd, J=14.4, 6.0 Hz, H-10), 2.67 (1H, br. d, J=14.4 Hz, H-10), 2.78 (1H,m, H-9), 3.27 (1H, m, H-20), 3.45 (1H, m, H-23), 3.48 (1H, s, OH), 3.85(2H, m, H-3, 23), 3.97 (1H, m, H-1), 4.72, 4.75 (each 1H, dd, J=47.5,9.7 Hz, CH₂F), 5.78 (1H, d, J=11.1 Hz, H-7), 6.40 (1H, d, J=11.1 Hz,H-6). ¹⁹F NMR (CDCl₃) δ: −240.3 (t, J=47.5 Hz). MS m/z (%): 454 (M⁺,24), 436 (9), 416 (3), 380.(1), 323 (16), 303 (4), 2.87 (3), 69 (100).UV λmax (EtOH): 243, 251, 261 nm. HR-MS m/z: 454.3087 (Calcd forC₂₆H₄₃FO₅: 454.3095).

109b: ¹H NMR (CDCl₃) δ: 0.56 (3H, s, H-18), 1.14 (3H, d, J=6.0 Hz,H-21), 1.23, 1.24 (each 3H, s, H-26, 27), 2.75-2.90 (3H, m, H-4, 9, 10),3.28 (1H, m, H-20), 3.45 (1H, m, H-23), 3.48 (1H, s, OH), 3.77 (1H, m,H-3), 3.84 (1H, m, H-23), 3.94 (1H, m, H-1), 4.70, 4.76 (each 1H) dd,J=48.0, 9.6 Hz, CH₂F), 5.83.(1H, d, J=11.3 Hz, H-7), 6.29 (1H, d, J=11.3Hz, H-6). ¹⁹F NMR (CDCl₃) δ: −240.4 (t, J=48.0 Hz). MS m/Z (%): 454 (M⁺,30), 436 (9), 434 (10), 416 (3), 323 (16), 303 (6), 69 (100). UV λmax(EtOH): 243, 251, 261 nm. HR-MS m/z: 454.3109 (Calcd for C₂₆H₄₃FO₅:454.3095).

Example 8820-epi-1α-[(t-butyldimethylsilyl)oxy]-2β-[(trimethylsilyl)oxy]-2α-methyl-and20-epi-1α-[(t-butyldimethylsilyl)oxy]-2α-[(trimethylsilyl)oxy]-2β-methyl-22-oxa-25-[(triethylsilyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 153a, 153b)

To a solution cooled to −78° C. of A-ring phosphine oxide 118 (214.7 mg,0.32 mmol, a mixture of ca. 1:1) in dry THF (3 mL) was added n-BuLi(202.9 μL, 0.32 mmol, 1.58 M solution in hexane), and the resultingsolution was stirred for 15 min. To this solution was added dropwise asolution of 22-oxa Grundmann's ketone 121 (54.6 mg, 0.14 mmol) in dryTHF (2 mL). The mixture was stirred for 3 h with warming gradually from−78° C. to −30° C., saturated NH₄Cl aqueous solution was added to themixture, and the mixture was extracted with AcOEt. The organic phase waswashed with saturated brine, dried over anhydrous MgSO₄, and distilledoff. The residue was purified by silica gel column chromatography (7 g,3% AcOEt/hexane) to afford Compound 153 (52.1 mg, 44%) as a mixture oftwo kinds of stereoisomers. The ratio of the isomer 153a to the isomer153b was ca. 3:1. Further, the unreacted starting material 121 (25.6 mg)was collected using 5% AcOEt/hexane.

153: ¹H NMR (CDCl₃) δ: 0.02-0.12 (21H, Si-Me×4, Si-Me₃), 0.5588 (3H, s,H-18), 0.5598 (6H, q, J=7.8 Hz, Si—CH₂CH₃×3), 0.83, 0.92 (each 9H, s,Si-tBu×2), 0.94 (9H, t, J=7.8 Hz, Si—CH₂CH₃×3), 1.08 (3H, d, J=5.9 Hz,H-21), 3.20-3.30 (2H, m), 3.55-3.80 (3H, m), 5.76, 5.82 (ca. 1:3) (1H,d, J=11.1 Hz, H-7), 6.04, 6.15 (ca. 3:1) (1H, d, J=11.1 Hz, H-6). MS m/z(%): 850 (M⁺, 3), 718 (74), 661 (5), 586 (100), 454 (3).

Example 89 1α,2β,25-trihydroxy-2α-methyl-22-oxa-19-norvitamin D₃(Compound 110a) and 1α,2α,25-trihydroxy-2β-methyl-22-oxa-19-norvitaminD₃ (Compound 110b)

To a solution of Compound 153 (52.1 mg, 0.061 mmol, a mixture of ca.3:1) in dry THF (1 mL) was added tetrabutylammonium fluoride (0.490 mL,0.490 mmol, 1 M solution in THF), and the mixture was stirred at roomtemperature for 18 h. The mixture was poured into ice water, andextracted with AcOEt. The organic phase was washed with saturated brine,dried over anhydrous MgSO₄, and distilled off. The residue was purifiedby silica gel column chromatography (10 g) using 70%/o AcOEt/hexane toyield Compound 110 (25.7 mg, 96%) as a mixture of two kinds ofstereoisomers. The ratio of the isomer 110a to the isomer 110b was ca.3:1. The mixture of Compounds 110a and 110b was separated and purifiedby HPLC (YMC-Pack ODS-AM SH-342-5, 150×20 mm, 30% H₂O/MeOH) to obtainCompounds 110a (14.7 mg) and 110b (4.43 mg), respectively.

110a: ¹H NMR (CDCl₃) δ: 0.55 (3H, s, H-18), 1.13 (3H, d, J=6.0 Hz,H-21), 1.22, 1.24 (each 3H, s, H-26, 27), 1.29 (3H, s, Me), 2.47 (1H,dd, J=14.1, 3.3 Hz, H-10), 2.64 (2H, m, H-4, 10), 2.78 (1H, m, H-9),3.27 (1H, m, H-20), 3.45 (1H, m, H-23), 3.58 (1H, s, OH), 3.72 (2H, m,H-1, OH), 3.78 (1H, m, H-3), 3.84 (1H, m, H-23), 5.79 (1H, d, J=11.1 Hz,H-7), 6.33 (1H, d, J=11.1 Hz, H-6). MS m/z (%): 436 (M⁺, 54), 418 (13),400 (8), 305 (15), 69 (100). UV λmax (EtOH): 243, 251, 261 nm.

100b: ¹H NMR (CDCl₃) δ: 0.54 (3H, s, H-18), 1.13 (3H, d, J=6.0 Hz,H-21), 1.23, 1.24 (each 3H, s, H-26, 27), 1.26 (3H, s, Me), 2.36 (1H,dd, J=14.4, 4.6 Hz), 2.54 (1H, br. d, J'13.8 Hz), 2.78 (1H, m, H-9),2.92 (1H, dd, J=14.5, 4.5 Hz), 3.26 (1H, m, H-20), 3.45 (1H, m, H-23),3.57 (1H, br. s, OH), 3.73 (3H, m, H-1, 3, OH), 3.84 (1H, m, H-23), 5.82(1H, d, J=11.1 Hz, H-7), 6.29 (1H, d, J=11.1 Hz, H-6). UV λmax (EtOH):243, 251, 261 nm.

Example 9024a,26a,27a-trihomo-1α-[(t-butyldimethylsilyl)oxy]-2α-[(trimethylsilyl)oxy]-and24a,26a,27a-trihomo-1α-[(t-butyldimethylsilyl)oxy]-2β-[(trimethylsilyl)oxy]-2β-[(trimethylsilyl)oxy]-22,24-dien-25-[(triethylsilyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 154a, 154b)

To a solution cooled to −78° C. of A-ring phosphine oxide 22 (260.0 mg,0.394 mmol, a mixture of ca. 2: 1) in dry THF (3 mL) was added n-BuLi(253 pi, 0.394 mmol, 1.56 M solution in hexane), and the resultingsolution was stirred for 15 min. To this solution was added slowly asolution of C/D-ring ketone 122 (101.8 mg, 0.235 mmol) in dry THF (1mL), and the mixture was stirred for 2 h at −78° C., saturated NH₄Claqueous solution was added to the mixture, and the mixture was extractedwith AcOEt. The organic phase was washed with saturated brine, driedover anhydrous MgSO₄, and distilled off. The residue was purified bysilica gel column chromatography (10 g) using 1% AcOEt/hexane to affordCompound 154 (106.4 mg, 52%) as a mixture of two kinds of stereoisomers.The ratio of the isomer 154a to the isomer 154b was ca. 3:2. Further,the unreacted starting material 122 (36.1 mg) was collected using 5%AcOEt/hexane.

NMR Data of the Mixture

154a (major product): ¹H NMR (CDCl₃) δ: 0.039, 0.051, 0.059, 0.064 (each3H, s, Si-Me×4), 0.12 (9H, s, Si-Me×3), 0.56 (3H, s, H-18), 0.56 (6H, q,J=7.9 Hz, SiCH₂×3), 0.82 (6H, t, J=7.5 Hz, H-26a, 27a), 0.868, 0.874(each 9H, s, Si-tBu×2), 0.94 (9H, t, J=7.9 Hz, SiCH₂CH₃×3), 1.06 (3H, d,J=6.6 Hz, H-21), 2.80 (1H, m, H-9), 3.53 (1H, m, H-2), 3.80 (1H, m,H-3), 3.88 (1H, m, H-1), 5.52 (1H, d, J=15.2 Hz, H-24a, overlapped withH-22), 5.81 (1H, d, J=11.1 Hz, H-7), 5.94 (1H, dd, J=14.9, 10.4 Hz,H-23), 6.05 (1H, dd, J=15.2, 10.4 Hz, H-24), 6.10 (1H, d, J=11.1 Hz,H-6).

154b (minor product): ¹H NMR (CDCl₃) δ: 0.039, 0.051,0.059, 0.064 (each3H, 5, Si-Me×4), 0.12 (9H, s, Si-Me×3), 0.54 (3H, s, H-18), 0.56 (6H, q,J=7.9 Hz, SiCH₂×3), 0.82 (6H, t, J=7.5 Hz, H-26a, 27a), 0.86, 0.89 (each9H, s, Si-tBu×2), 0.94 (9H, t, J=7.9 Hz, SiCH₂CH₃×3), 1.06 (3H, d, J=6.6Hz, H-21), 2.80 (1H, m, H-9), 3.59 (1H, m, H-2), 3.80 (1H, m, H-3), 3.94(1H, m, H-1), 5.52 (1H, d, J=15.2 Hz, H-24a, overlapped with H-22), 5.78(1H, d, J=11.1 Hz, H-7), 5.94 (1H, dd, J=14.9, 10.4 Hz, H-23), 6.05 (1H,dd, J=15.2, 10.4 Hz, H-24), 6.13 (1H, d, J=11.1 Hz, H-6). MS m/z (%) ofthe mixture: no M⁺, 740 (33), 683 (7), 608 (65), 551 (17), 505 (43),4.59 (18), 324 (31), 149 (100), 75 (99).

Example 91 24a,26a,27a-trihomo-1α,2α,25-trihydroxy- and24a,26a,27a-trihomo-1α,2β,25-trihydroxy-22,24-dien-19-norvitamin D₃(Compounds 155a, 155b)

To a solution of Compound 154 (55 mg, 0.063 mmol, a mixture of ca. 3:2)in dry THF (1 mL) were added Et₃N (20 μL) and tetrabutylammoniumfluoride (504 μL, 0.504 mmol, 1.0 M solution in THF), and the resultingsolution was stirred at room temperature for 4 h. The mixture was pouredinto ice water and extracted with AcOEt. The organic phase was washedwith saturated brine, and dried over anhydrous MgSO₄. Removal of thesolvent in vacuo afforded the residue, which was purified by silica gelcolumn chromatography (5 g, 2% MeOH/AcOEt) to yield Compound 155 (28.0mg, 97%) as a mixture of two kinds of stereoisomers. The ratio of theisomer 155a to the isomer 155b was ca. 3:2.

NMR Data of the mixture

155a: ¹H NMR (CDCl₃) δ: 0.57 (3H, s, H-18), 0.87 (6H, t, J=7.4 Hz,H-26a, 27a), 1.05 (3H, d, J=6.6 Hz, H-21), 1.55, 1.56 (each 2H, d, J=7.4Hz, H-26, 27), 2.62 (1H, dd, J=12.8, 4.1 Hz, H-4), 2.80 (1H, m, H-9),2.89 (1H, dd, J=14.7, 4.3 Hz, H-10), 3.53 (1H, d, J=8.2, 2.9 Hz, H-2),3.79 (1H, m, H-3), 4.09 (1H, m, H-1), 5.53 (1H, d, J=15.2 Hz, H-24a,overlapped with H-22), 5.80 (1H, d, J=11.1 Hz, H-7), 5.98 (1H, dd,J=15.0, 10.3 Hz, H-23), 6.15 (1H, dd, J=15.2, 10.3 Hz, H-24), 6.37 (1H,d, J=11.1 Hz, H-6).

155b: ¹H NMR (CDCl₃) δ: 0.57 (3H, s, H-18), 0.87 (6H, t, J=7.4 Hz,H-26a, 27a), 1.05 (3H, d, J=6.6 Hz, H-21), 1.55, 1.56 (each 2H, d, J=7.4Hz, H-26, 27), 2.43 (2H, m, H-4), 2.80 (1H, m, H-9), 3.07 (1H, dd,J=13.2, 4.9 Hz, H-10), 3.48 (1H, dd, J=8.8, 3.0 Hz, H-2), 3.67 (1H, m,H-3), 4.09 (1H, m, H-1), 5.53 (1H, d, J=15.2 Hz, H-24a, overlapped withH-22), 5.83 (1H, d, J=11.1 Hz, H-7), 5.98 (1H, dd, J=15.0, 10.3 Hz,H-23), 6.15 (1H, dd, J=15.2, 10.3 Hz, H-24), 6.29 (1H, d, J=11.1 Hz,H-6). MS m/z (%) of the mixture: 458 (M⁺, 33), 440 (95), 422 (14), 404(16), 386 (52), 318 (40), 289 (90), 237 (44), 149 (100).

Example 9224a,26a,27a-trihomo-1α-[(t-butyldimethylsilyl)oxy]-2α-hydroxy- and24a,26a,27a-trihomo-1α-[(t-butyldimethylsilyl)oxy]-2β-hydroxy-22,24-dien-25-[(t-butyldimethylsilyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 156a, 156b)

To a solution of Compound 155 (48.0 mg, 0.105 mmol, a mixture of ca.3:2) in dry DMF (1 mL) were added Et₃N (117 μL, 0.840 mmol),tert-butyldimethylsilyl chloride (63.9 mg, 0.424 mmol) and4,4-(dimethylamino)pyridine (6.4 mg, 0.052 mmol), and the resultingsolution was stirred at room temperature for 2 h. The reaction mixturewas poured into ice water, and extracted with AcOEt. The organic phasewas washed with saturated brine, dried over anhydrous Na₂SO₄, anddistilled off. The residue was purified by silica gel columnchromatography (5 g, 5% AcOEt/hexane) to yield Compound 156 (55;3 mg,66%) as a mixture of two kinds of stereolsomers. The ratio of the isomer156a to the isomer 156b was ca. 3:2.

NMR Data of the Mixture

156a (major product): ¹H NMR (CDCl₃) δ: 0.06-0.10 (18H, Si-Me×6), 0.57(3H, s, H-18), 0.87 (6H, t, J=7.5 Hz, H-26a, 27a), 0.86-0.92 (27H,Si-tBu×3), 1.06 (3H, d, J=6.6 Hz, H-21), 1.54, 1.55 (each 2H, d, J=7.5Hz, H-26, 27), 2.80 (1H, m, H-9), 3.51 (1H, d, H-2), 3.92 (1H, m, H-3),4.00 (1H, m, H-1), 5.53 (1H, d, J=15.3 Hz, H-24a), 5.55 (1H, dd, J=15.2,8.5 Hz, H-22), 5.79 (1H, d, J=11.1 Hz, H-7), 5.98 (1H, dd, J=15.2, 10.4Hz, H-23), 6.14 (2H, m, H-6, 24).

156b (minor product): ¹H NMR (CDCl₃) δ: 0.06-0.10 (18H, Si-Me×6), 0.56(3H, s, H-18), 0.87 (6H, t, J=7.5 Hz, H-26a, 27a), 0.86-0.92 (27H,Si-tBu×3), 1.06 (3H, d, J=6.6 Hz, H-21), 1.54, 1.55 (each 2H, d, J=7.5Hz, H-26, 27), 2.80 (1H, m, H-9), 3.59 (1H, m, H-2), 4.00 (2H, m, H-1,3), 5.53 (1H, d, J=15.3 Hz, H-24a), 5.55 (1H, dd, J=15.2, 8.5 Hz, H-22),5.79 (1H, d, J=11.1 Hz, H-7), 5.98 (1H, dd, J=15.2, 10.4 Hz, H-23), 6.14(2H, m, H-6, 24). MS m/z (%) of the mixture: no M⁺, 668 (6), 611 (2),536 (3), 479 (12), 386 (6), 149 (100), 75 (79).

Example 9324a,26a,27a-trihomo-1α-[(t-butyldimethylsilyl)oxy]-2α-[2-(t-butyldimethylsilyl)oxy]-ethoxy-and24a,26a,27a-trihomo-1α-[(t-butyldimethylsilyl)oxy]-2β-[2-(t-butyldimethylsilyl)oxy]-ethoxy-22,24-dien-25-[(t-butyldimethylsilyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 157a, 157b)

To a solution cooled to 0° C. of Compound 156 (52.4 mg, 0.065 mmol, amixture of ca. 3:2) in dry DMF (1 mL) were added NaH (78.5 mg, 1.962mmol, 60% paraffin liquid (dispersion in mineral oil)) and(2-bromoethoxy)-tert-butyldimethylsilane (68 μL, 0.317 mmol), and theresulting solution was stirred vigorously. After 18 h, the reactionmixture was poured into ice water, and then extracted with AcOEt/hexane(1:1). The organic phase was washed with saturated brine, dried overanhydrous MgSO₄, and distilled off. The residue was purified by silicagel column chromatography (10 g, 1-10% AcOEt/hexane) to afford Compound157 (44.7 mg, 71%) as a mixture of kinds of stereoisomers. The ratio ofthe isomer 157a to the isomer 157b was ca. 3:2.

157: ¹H NMR (CDCl₃) δ: 0.05-0.10 (24H, Si-Me×8), 0.55, 0.57 (ca. 2:3)(3H, s, H-18), 0.85-0.92 (42H, 4×Si-tBu, H-26a, 27a), 1.05 (3H, d, J=6.6Hz, H-21), 1.54, 1.55 (each 2H, d, J=7.5 Hz, H-26, 27), 2.80 (1H, m,H-9), 3.18-4.45 (7H, m, OCH₂CH₂O, H-1, 3), 5.52 (1H, d, J=15.1 Hz,H-24a), 5.54 (1H, dd, J=15.0, 8.6 Hz, H-22), 5.79 (1H, H-7), 5.97 (1H,dd, J=15.0, 10.4 Hz, H-23), 6.15 (2H, m, H-6, 24). MS m/z (%): no M⁺,649 (14), 651 (11), 562 (12), 519 (24), 233 (100).

Example 94 24a,26a,27a-trihomo-1α,25-dihydroxy-2α-(2-hydroxyethoxy)- and24a,26a,27a-trihomo-1α,25-dihydroxy-2β-(2-hydroxyethoxy)-22,24-dien-19-norvitaminD₃ (Compounds 111a, 111b)

To a solution of Compound 157 (42.0 mg, 0.044 mmol, a mixture of ca.3:2) in dry THF (1 mL) were added Et₃N (30 μL) and tetrabutylammoniumfluoride (350 μL, 0.350 mmol, 1.0 M solution in THF), and the resultingsolution was stirred at room temperature for 5 h. The mixture was pouredinto ice water, and extracted with AcOEt. The organic phase was washedwith saturated brine, dried over anhydrous Na₂SO₄, and distilled off.The residue was purified by silica gel column chromatography (5 g, 2%MeOH/AcOEt) to yield a mixture of Compounds 111a and 111b (20.0 mg,91%). The mixture of 111a and 111b was separated and purified by HPLC(YMC-Pack ODS-AM SH-342-5, 150×20 mm, 20% H₂O/MeOH) to obtain Compounds111a (9.4 mg) and 111b (8.3 mg), respectively.

111a: ¹H NMR (CDCl₃) δ: 0.57 (3H, s, H-18), 0.86 (6H, t, J=7.4 Hz,H-26a, 27a), 1.04 (3H, d, J=6.6 Hz, H-21), 1.54, 1.56 (each 2H, d, J=7.4Hz, H-26, 27), 2.61 (1H, dd, J=13.4, 4.4 Hz, H-4), 2.80 (1H, m, H-9),2.86 (1H, dd, J=14.4, 4.8 Hz, H-10), 3.32 (1H, dd, J=8.0, 2.5 Hz, H-2),2.72, 3.12, 3.48 (each 1H, br. s, OH×3), 3.67-3.81 (4H, m, OCH₂CH₂O),3.93 (1H, m, H-3), 4.15 (1H, m, H-1), 5.53 (1H, d, J=15.3 Hz, H-24a,overlapped with H-22), 5.81 (1H, d, J=11.1 Hz, H-7), 5.97 (1H, dd,J=15.0, 10.3 Hz, H-23), 6.14 (1H, dd, J=15.3, 10.3 Hz, H-24), 6.33 (1H,d, J=11.1 Hz, H-6). UV λmax (EtOH): 235 (ε 44,000), 243 (ε 44,200), 251(ε 38,000), 261 (ε 23,800) nm. MS m/z (%): 502 (M⁺, 11), 484 (62), 466(33), 448 (7), 386 (17), 333 (40), 237 (29), 149 (100), 133 (43), 93(49). HR-MS m/z: 502.3658 (Calcd for C₃₁H₅₀O₅: 502.3658).

111b: ¹H NMR (CDCl₃) δ: 0.56 (3H, s, H-18), 0.86 (6H, t, J=7.5 Hz,H-26a, 27a), 1.05 (3H, d, J=6.6 Hz, H-21), 1.55, 1.56 (each 2H, d, J=7.5Hz, H-26, 27), 2.34, 2.47 (each 1H, m, H-4), 2.64 (1H, br. s, OH), 2.80(1H, m, H-9), 3.07 (1H, dd, J=13.2, 4.0 Hz, H-10), 3.27 (1H, dd, J=8.7,2.6 Hz, H-2), 3.64-3.86 (5H, m, OCH₂CH₂O, H-1), 4.16 (1H, m, H-3), 5.35(1H, d, J=15.3 Hz, H-24a, overlapped with H-22), 5.83 (1H, d, J=11.1 Hz,H-7), 5.97 (1H, dd, J=15.0, 10.3 Hz, H-23), 6.15 (1H, dd, J=15.3, 10.3Hz, H-24), 6.26 (1H, d, J=11.1 Hz, H-6). UV λmax (EtOH): 235 (ε 44,000),243 (ε 44,500), 251 (ε 38,900), 261 (ε 24,000) nm. MS m/z (%): 502 (M⁺,13), 484 (78), 466 (39), 448 (7), 386 (13), 333 (48), 237 (27), 149(100), 133 (46), 93 (49). HR-MS m/z: 502.3664 (Calcd for C₃₁H₅₀O₅:502.3658).

Example 95 E-isomer and Z-isomer of24a,26a,27a-trihomo-1α-[(t-butyldimethylsilyl)oxy]-2-[2-(t-butyldimethylsilyl)oxy]-ethylidene-22,24-dien-25-[(triethylsilyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 15.8a, 158b)

To a solution cooled to −78° C. of A-ring phosphine oxide 119 (119.5 mg,0.164 mmol, a mixture of ca. 4:1) in dry THF (2 mL) was added n-BuLi(105 μL, 0.164 mmol, 1.56 M solution in hexane), and the resultingsolution was stirred for 15 min. To this solution was added slowly asolution of C/D-ring ketone 122 (47.4 mg, 0.109 mmol) in dry THF (1 mL),and the mixture was stirred for 2 h at −78° C., saturated NH₄Cl aqueoussolution was added to the mixture, and the mixture was extracted withAcOEt. The organic phase was washed with saturated brine, dried overanhydrous MgSO₄, and distilled off. The residue was purified by silicagel column chromatography (10 g) using 1% AcOEt/hexane to affordCompound 158 (27.7 mg, 27%) as a mixture of two kinds of stereoisomers.The ratio of the isomer 158a to the isomer 158b was ca. 6:1. Further,the unreacted starting material 122 (27 mg, 57%) was collected using 5%AcOEt/hexane.

158: ¹H NMR (CDCl₃) δ: 0.01-0.08 (18H, Si-Me×6), 0.571 (3H, s, H-18),0.569 (6H, q, J=7.9 Hz, SiCH₂×3), 0.83 (6H, t, J=7.5 Hz, H-26a, 27a),0.84, 0.90, 0.92 (each 9H, s, Si-tBu×3), 0.94 (9H, t, J=7.9 Hz,SiCH₂CH₃×3), 1.06 (3H, d, J=6.6 Hz, H-21), 2.80 (1H, m, H-9), 2.97, 3.28(ca. 6: 1) (1H, dd, J=12.5, 4.7 Hz, H-10), 4.24-4.47 (3H, m, H-1 or 3,CH₂OH), 4.79, 4.84 (ca. 6:1) (1H, m, H-1 or 3), 5.52 (1H, dd, J=14.9,8.3 Hz, H-22), 5.53 (1H, d, J=15.2 Hz, H-24a), 5.61 (1H, m, C═CH), 5.87(1H, d, J=11.1 Hz, H-7), 5.95 (1H, dd, J=14.9, 10.4 Hz, H-23), 6.06 (1H,dd, J=15.2, 10.4 Hz, H-24), 6.13 (1H, d, J=11.1 Hz, H-6).

Example 96 E-isomer and Z-isomer of24a,26a,27a-trihomo-1α,25-dihydroxy-2-[2-(hydroxy)-ethylidene]-22,24-dien-19-norvitaminD₃ (Compounds 112a, 112b)

To a solution of Compound 158 (56 mg, 0.0595 mmol, a mixture of ca. 6:1)in dry THF (1 mL) were added Et₃N (40 μL) and tetrabutylammoniumfluoride (476 μL, 0.476 mmol, 1.0 M solution in THF), and the mixturewas stirred at room temperature for 20 h. The mixture was poured intoice water, and extracted with AcOEt. The organic phase was washed withsaturated brine, dried over anhydrous Na₂SO₄, and distilled off. Theresidue was purified by silica gel column chromatography (5 g, 2%MeOH/AcOEt) to yield a mixture of Compounds 112a and 112b (23.0 mg, 80%,ca. 10:1). The mixture of 112a and 112b was separated and purified byHPLC (LiChrosorb Si 60, Hibar RT 250-10, 250×10 mm,hexane:CH₂Cl₂:MeOH=50:50:4) to obtain Compounds 112a (17.1 mg, E-isomer)and 112b (1.9 mg, Z-isomer), respectively.

112a: ¹H NMR (CDCl₃) δ: 0.56 (3H, s, H-18), 0.87 (6H, t, J=7.5, H-26a,27a), 1.05 (3H, d, J=6.5 Hz, H-21), 1.55, 1.56 (each 2H, d, J=7.5 Hz,H-26, 27), 2.34, 2.44 (each 1H, m, H-4), 2.81 (1H, m, H-9), 3.14 (1H, d,J=12.5, 4.3 Hz, H-10), 3.38, 3.74 (each 1H, br. s, OH×2), 4.09 (1H, dd,J=12.3, 5.2 Hz, CH₂OH), 4.34 (2H, m, H-1, CH₂OH), 4.80 (1H, m, H-3),5.53 (1H, d, J=15.4 Hz, H-24a, overlapped with H-22), 5.75 (1H, m,C═CH), 5.88 (1H, d, J=11.1 Hz, H-7), 5.97 (1H, dd, J=15.0, 10.4 Hz,H-23), 6.15 (1H, dd, J=15.4, 10.4 Hz, H-24), 6.27 (1H, d, J=11.1 Hz,H-6). UV λmax (EtOH): 236 (ε 47,300), 245 (ε 48,000), 254 (ε 43,200),264 (ε 27,200) nm. MS m/z (%): 484 (M⁺, 7), 466 (15), 448 (17), 430(44), 412 (34), 279 (33), 263 (25), 149 (100), 133 (35), 93 (38). HR-MSm/z: 484.3526 (Calcd for C₃₁H₄₈O₄: 484.3553).

112b: ¹H NMR (CDCl₃) δ: 0.57 (3H, s, H-18), 0.87 (6H, t, J=7.5 Hz,H-26a, 27a), 1.05 (3H, d, J=6.6 Hz, H-21), 1.55, 1.56 (each 2H, d, J=7.5Hz, H-26, 27), 2.22 (1H, m, H-4), 2.33 (1H, m, H-10), 2.70,(1H, dd,J=13.0, 4.7 Hz, H-4), 2.82 (2H, m, H-9,10), 4.25 (1H, dd, J=12.6, 6.4Hz, CH₂OH), 4.38 (1H, dd, J=12.6, 7.3 Hz, CH₂OH), 4.46 (1H, m, H-3),4.87 (1H, t, J=4.2 Hz, H-1), 5.54 (1H, d, J=15.3 Hz, H-24a, overlappedwith H-22), 5.84 (2H, m, H-7, C═CH), 5.98 (1H, dd, J=15.0, 10.3 Hz,H-23), 6.15 (1H, dd, J=15.3, 10.3 Hz, H-24), 6.40 (1H, d, J=11.1 Hz,H-6). MS m/z (%): 484 (M⁺, 4), 466 (12), 448 (16), 430 (44), 412 (38),279 (35), 263 (32), 149 (100), 133 (39), 93 (42). HR-MS m/z: 484.3561(Calcd for C₃₁H₄₈O₄: 484.3553).

Example 9724a,26a,27a-trihomo-1α-[(t-butyldimethylsilyl)oxy]-2β,2′-epoxy- and24a,26a,27a-trihomo-1α-[(t-butyldimethylsilyl)oxy]-2α,2′-epoxy-22,24-dien-25-[(triethylsilyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 159a, 159b)

To a solution cooled to −78° C. of A-ring phosphine oxide 13 (260 mg,0.434 mmol, a mixture of ca. 3:1) in dry THF (2 mL) was added n-BuLi(276 μL, 0.436 mmol, 1.58 M solution in hexane), and the resultingsolution was stirred for 15 min. To this solution was added slowly asolution of C/D-ring ketone 122 (100 mg, 0.231 mmol) in dry THF (1.5mL). The mixture was stirred for 3 h with warming gradually from −78° C.to −20° C., saturated NH₄Cl aqueous solution was added to the mixture,and the mixture was extracted with AcOEt. The organic phase was washedwith saturated brine, dried over anhydrous MgSO₄, and distilled off Theresidue was purified by silica gel column chromatography (10 g, 2%AcOEt/hexane) to afford Compound 159 (31.3 mg, 17%) as a mixture of twokinds of stereoisomers. The ratio of the isomer 159a to the isomer 159bwas ca. 10:1. Further, the unreacted starting material 122 (48.0 mg) wascollected using 5% AcOEt/hexane.

159: ¹H NMR (CDCl₃) δ: 0.02, 0.05 (each 3H, s, Si-Me×2), 0.06 (6H,Si-Me×2), 0.567 (6H, q, J=7.9 Hz, SiCH₂×3), 0.570 (3H, s, H-18), 0.82(6H, t, J=7.5 Hz, H-26a, 27a), 0.86, 0.87 (each 9H, s, Si-tBu×2), 0.94(9H, t, J=7.9 Hz, SiCH₂CH₃×3), 1.06 (3H, d, J=6.6 Hz, H-21), 3.80 (1H,m), 3.87 (1H, m), 5.52 (1H, d, J=15.0 Hz, H-24a, overlapped with H-22),5.81 (1H, d, J=11.1, H-7), 5.80-6.08 (3H, m), 6.21, 6.27 (ca. 10:1) (1H,d, J=11.1 Hz, H-7).

Example 98 24a,26a,27a-trihomo-1α,25-dihydroxy-2β,2′-epoxy- and24a,26a,27a-trihomo-1α,25-dihydroxy-2α,2′-epoxy-22,24-dien-19-norvitaminD₃ (Compounds 113a, 113b), and24a,26a,27a-trihomo-1α,2β,25-trihydroxy-2α-methyl- and24a,26a,27a-trihomo-1α,2α,25-trihydroxy-22,24-dien-19-norvitamin D₃(Compounds 114a, 114b)

To a solution of Compound 159 (34.0 mg, 0.042 mmol, a mixture of ca.10:1) in dry THF (1 mL) were added Et₃N (75 Si) and tetrabutylammoniumfluoride (251 μL, 0.24 mmol, 1.0 M solution in THF), and the mixture wasstirred at room temperature for 7.5 h. The mixture was poured into icewater, and extracted with AcOEt. The organic phase was washed withsaturated brine, dried over anhydrous MgSO₄, and distilled off. Theresidue was purified by silica gel column chromatography (5 g) with 50%AcOEt/hexane to yield Compound 114 (1.5 mg, 7%) as a mixture of twokinds of stereoisomers, and with 70% AcOEt/hexane to give Compound 113(14.7 mg, 75%) as a mixture of two kinds of stereoisomers. The exactratio of these isomers was not determined by ¹H NMR spectrum of thesemixtures, since a signal derived from each isomer was overlapped. Themixture of 113a and 113b was separated and purified by HPLC (LiChrosorbSi 60, Hibar RT 250-10, 250×10 mm, hexane:CH₂Cl₂:MeOH=40:60:5) to obtainCompounds 113a (4.73 mg) and 113b (628 μg), respectively.

113a: ¹H NMR (CDCl₃) δ: 0.57 (3H, s, H-18), 0.87 (6H, t, J=7.4 Hz,H-26a, 27a), 1.06 (3H, d, J=6.5 Hz, H-21), 2.31 (1H, dd, J=13.4, 8.6 Hz,H-10), 2.40 (1H, dd, J=13.6, 6.2 Hz, H-4), 2.61 (1H, dd, J=13.6, 3.3 Hz,H-4), 2.80 (1H, m, H-9), 2.84 (1H, d, J=4.7 Hz, OCH), 2.95 (1H, dd,J=13.4, 4.1 Hz, H-10), 3.08 (1H, d, J=4.7 Hz, OCH), 5.53 (1H, d, J=15.5Hz, H-24a, overlapped with H-22), 5.68 (1H, d, J=11.1 Hz, H-7), 5.97(1H, dd, J=15.0, 10.3 Hz, H-23), 6.15 (1H, dd, J=15.5, 10.3 Hz, H-24),6.39 (1H, d, J=11.1 Hz, H-6). UV λmax (EtOH): 235, 243, 251, 261 nm.

113b: ¹H NMR (CDCl₃) δ: 0.58 (3H, s, H-18), 0.87 (6H, t, J=7.6 Hz,H-26a, 27a), 1.06 (3H, d, J=6.6 Hz, H-21), 2.28-2.38 (2H, m, H-4, 10),2.71 (1H, dd, J=13.8, 3.5 Hz, H-4), 2.80 (1H, m, H-9), 2.86 (1H, dd,J=13.2, 4.2 Hz, H-10), 2.94, 2.99 (each 1H, d, J=4.7 Hz, OCH₂), 5.53(1H, d, J=15.2 Hz, H-24a, overlapped with H-22), 5.87 (1H, d, J=11.0 Hz,H-7), 5.98 (1H, dd, J=15.0, 10.3 Hz, H-23), 6.16 (1H, dd, J=15.2, 10.3Hz, H-24), 6.38 (1H, d, J=11.0 Hz, H-6). UV λmax (EtOH): 234, 243, 251,261 nm.

114: ¹H NMR (CDCl₃) δ: 0.55 (3H, s, H-18), 0.88 (6H, t, J=7.5 Hz, H-26a,27a), 1.05 (3H, d, J=6.6 Hz, H-21), 3.87, 3.97 (each 1H, m, H-1, 3),4.72, 4.76 (each 1H, dd, J=48.0, 9.7 Hz, CH₂F), 5.53 (1H, d, J=15.1 Hz,H-24a, overlapped with H-22), 5.80 (1H, d, J=11.2 Hz, H-7), 5.97 (1H,dd, J=15.0, 10.3 Hz, H-23), 6.15 (1H, dd, J=15.1, 10.3 Hz, H-24), 6.40(1H, d, J=11.2 Hz, H-6). ¹⁹F NMR (CDCl₃) δ: −240.5 (t, J=48.0 Hz).

Example 9924a,26a,27a-trihomo-1α-[(t-butyldimethylsilyl)oxy]-2β-[(trimethylsilyl)oxy]-2α-methyl-and24a,26a,27a-trihomo-1α-[(t-butyldimethylsilyl)oxy]-2α-[(trimethylsilyl)oxy]-2β-methyl-22,24-dien-25-[(triethylsilyl)oxy]-19-norvitaminD₃ t-butyldimethylsilyl ether (Compounds 160a, 160b)

To a solution cooled to −78° C. of A-ring phosphine oxide 118 (253.9 mg,0.377 mmol, a mixture of ca. 1:1) in dry THF (2.5 mL) was added n-BuLi(238.6 μL, 0.377 mmol, 1.58 M solution in hexane), and the resultingsolution was stirred for 15 min. To this solution was added slowly asolution of C/D-ring ketone 122 (84.0 mg, 0.194 mmol) in dry THF (1.5mL). The mixture was stirred for 3 h with warming gradually from −78° C.to −30° C., saturated NH₄Cl aqueous solution was added to the mixture,and the mixture was extracted with AcOEt. The organic phase was washedwith saturated brine, dried over anhydrous MgSO₄, and distilled off Theresidue was purified by silica gel column chromatography (6 g, 1%AcOEt/hexane) to afford Compound 160 (44.6 mg, 26%) as a mixture of twokinds of stereoisomers. The ratio of the isomer 160a to the isomer 160bwas ca. 1:2. Further, the unreacted starting material 122 (47.0 mg) wascollected using 5% AcOEt/hexane.

160: ¹H NMR (CDCl₃) δ: 0.02-0.09 (12H, Si-Me×4), 0.11, 0.12 (ca. 1:2)(9H, s, Si-Me×3), 0.569 (3H, s, H-18), 0.570 (6H, q, J=7.6 Hz,Si—CH₂CH₃×3), 0.82 (6H, t, J=7.5 Hz, H-26a, 27a), 0.83, 0.92 (each 9H,s, Si-tBu×2), 0.94 (9H, t, J=7.6 Hz, Si—CH₂CH₃×3), 1.06 (3H, d, J=6.6Hz, H-21), 3.56 (1H, m), 3.60, 3.70 (ca. 2:1) (1H, m), 5.52 (1H, d,J=15.2 Hz, H-24a, overlapped with H-22), 5.78, 5.84 (ca. 1:2) (1H, d,J=11.2 Hz, H-7), 5.90-6.15 (3H,

Example 100 24a,26a,27a-trihomo-1α,2β,25-trihydroxy-2α-methyl- and24a,26a,27a-trihomo-1α,2β,25-trihydroxy-2β-methyl-22,24-dien-19-norvitaminD₃ (Compounds 115a, 115b)

To a solution of Compound 160 (56.0 mg, 0.063 mmol, a mixture of ca.2:1) in dry THF (1.5 mL) were added Et₃N (75 μL), and tetrabutylammoniumfluoride (505 μL, 0.505 mmol, 1.0 M solution in THF), and the mixturewas stirred at room temperature for 24 h. The mixture was poured intoice water, and extracted with AcOEt. The organic phase was washed withsaturated brine, dried over anhydrous MgSO₄, and evaporated in vacuo.The residue was purified by silica gel column chromatography (5 g, 60%AcOEt/hexane) to yield

Compound 115 as a Mixture of Two Isomers (25.1 mg, 84%, a Mixture of ca.5:4).

The mixture of 115a and 115b was purified by HPLC (YMC-Pack ODS-AMSH-342-5, 150×20 mm, 20% H₂O/MeOH) to afford Compounds 115a (5.25 mg)and 115b (6.68 mg), respectively.

115a: ¹H NMR (CDCl₃) δ: 0.56 (3H, s, H-18), 0.88 (6H, t, J=7.5 Hz,H-26a, 27a), 1.05 (3H, d, J=6.6 Hz, H-21), 2.37 (1H, dd, J=14.4, 4.4 Hz,H-4), 2.54 (1H, br. d, J=14.4 Hz, H-4), 2.80 (1H, m, H-9), 2.94 (1H, dd,J=13.5, 4.4 Hz, H-10), 3.73 (2H, m, H-1, 3), 5.53 (1H, d, J=15.4 Hz,H-24a, overlapped with H-22), 5.84 (1H, d, J=11.2 Hz, H-7), 5.97 (1H,dd, J=15.0, 10.3 Hz, H-23), 6.15 (1H, dd, J=15.4, 10.3 Hz, H-24), 6.29(1H, d, J=11.2 Hz, H-6). MS m/z (%): 472 (M⁺, 13), 454 (100), 436 (38),418 (29), 400 (46). UV λmax (EtOH): 235, 243, 252, 261 nm.

115b: ¹H NMR (CDCl₃) δ: 0.57 (3H, s, H-18), 0.87 (6H, t, J=7.5 Hz,H-26a, 27a), 1.05 (3H, d, J=6.6 Hz, H-21), 2:48 (1H, dd, J=14.2, 3.2 Hz,H-10), 2.63 (1H, dd, J=14.2, 6.4 Hz, H-10), 2.66 (1H, dd, J=14.0, 4.0Hz, H-4), 2.80 (1H, m, H-9), 3.72, 2.78 (each 1H, m, H-1, 3), 5.53 (1H,d, J=15.4 Hz, H-24a, overlapped with H-22), 5.82 (1H, d, J=11.1 Hz,H-7), 5.98 (1H, dd, J=15.0, 10.3 Hz, H-23), 6.15 (1H, dd, J=15.4, 10.3Hz, H-24), 6.33 (1H, d, J=11.1 Hz, H-6). MS m/z (%): 472 (M⁺, 2), 454(100), 436 (18), 418 (10), 400 (12). UV λmax (EtOH): 235, 243, 251, 261nm.

Example of Examination Binding Assay for Calf Thymus Vitamin D Receptor(VDR)

The binding ability of the compounds of the present inventions describedin the above Examples to vitamin D receptor (VDR) derived from calfthymus was evaluated.

The binding assay was carried out according to the manufacturer'sinstruction of Yamasa Shoyu Co., Ltd. as follows.

An EtOH solution (sample) containing an increasing amount of each1α,25-dihydroxyvitamin D₃ (as a standard reference material), andCompounds YI-1a, YI-1b, YI-2a, YI-3a, YI-3b, YI-4a, YI-4b, YI-5a, YI-5b,20-Epi-YI-1a, 20-Epi-YI-1b, 20-Epi-YI-2a, 20-Epi-YI-3a, 20-Epi-YI-4a,20-Epi-YI-4b, 20-Epi-YI-5a, 20-Epi-YI-5b, 20-Epi-YI-6a, 20-Epi-YI-6b,20-Epi-YI-7a, 20-Epi-YI-7b, 20-Epi-YI-8a, and 20-Epi-YI-8b was prepared,that is, dilution series were prepared wherein final concentrations ofeach compounds in a mixture, which is prepared by following step, ofreceptor solutions, samples, and [³H]-1α,25-dihydroxyvitamin D₃solutions are 100 nM, 30 nM 10 nM, 1 nM, 300 pM, 100 pM, 30 pM, 10 pM, 3pM, and 1 pM.

Freeze-dried calf thymus vitamin D receptors (Lot. No. 111931) werepurchased from Yamasa Shoyu Co., Ltd. (Choshi, Chiba, Japan) and weredissolved in 45 mL of phosphate buffer (0.3 M KCl, 0.05 M K₂HPO₄—KH₂PO₄,pH 7.4) just before use to use as a receptor solution.

50 μL of sample of Compounds YI-1a, YI-1b, YI-2a, YI-3a, YI-3b, YI-4a,YI-4b, YI-5a, YI-5b, 20-Epi-YI-1a, 20-Epi-YI-1b, 20-Epi-YI-2a,20-Epi-YI-3a, 20-Epi-YI-4a, 20-Epi-YI-4b, 20-Epi-YI-5a, 20-Epi-YI-5b,20-Epi-YI-6a, 20-Epi-YI-6b, 20-Epi-YI-7a, 20-EPi-YI-7b, 20-Epi-YI-8a,20-Epi-YI-8b, or 1α,25-dihydroxyvitamin D₃ and 500 μL of the receptorsolution were pipetted into glass culture tubes. The mixture wasvortexed 2-3 times, and incubated for 1 h at room temperature. To eachtubes, [³H]-1α,25-dihydroxyvitamin D₃ (ca. 10000 dpm) in 50 μL of EtOHwas added, the mixture was vortexed 2-3 times, and the whole mixture wasincubated for 18 h at 4° C. (in a refrigerator). Then, 200 μL of DCC(dextran-coated charcoal; purchased from Yamasa Shoyu) was added to eachtubes, and allowed to stand for 30 min at 4° C. Bound and free[³]-1α,25-dihydroxyvitamin D₃ were separated by centrifugation at 3000rpm for 15 min at 4° C. Aliquots (500 μL) of the supernatant were putinto vial bottles from each tube, and were mixed with 10 mL of ACS-IIfluid scintillator (Amersham, Buckinghamshire, U.K.) and submitted forradioactivity counting.

The relative binding affinity of the vitamin D derivatives of thepresent inventions to VDR was calculated regarding binding affinity of1α,25-dihydroxyvitamin D₃ to VDR as 1. The following equation was usedto calculate the relative VDR binding affinity:X=y/x

X: the relative binding affinity of the compound of the presentinventions to VDR

y: the concentration of 1α,25-dihydroxyvitamin D₃ required for 50%inhibition of binding [³H]-1α,25-dihydroxyvitamin D₃ to VDR

x: the concentration of the compound of the present inventions requiredfor 50% inhibition of binding [³H]-1α,25-dihydroxyvitamin D₃ to VDR

TABLE 1 Compounds VDR affinity YI-1a 1/23 YI-1b 1/290 YI-2a 1/43 YI-3a1/3 YI-3b 1/730 YI-4a 1/50 YI-4b 1/2000 YI-5a 1/26 YI-5b 1/82020-Epi-YI-1a 1/2 20-Epi-YI-1b 1/5 20-Epi-YI-2a 2 20-Epi-YI-3a 120-Epi-YI-4a 1/20 20-Epi-YI-4b 1/1000 20-Epi-YI-5a 1/5 20-Epi-YI-5b 1/1020-Epi-YI-6a 1 20-Epi-YI-6b 5 20-Epi-YI-7a 1 20-Epi-YI-7b 1/520-Epi-YI-8a 1.6 20-Epi-YI-8b 1/50

INDUSTRIAL APPLICABILITY

The compounds represented by the formulae (I) and (IV) of the presentinvention are a novel compound and may be useful as pharmaceuticalagents for diseases accompanying with abnormal cell differentiation.Also, the compound of the present invention may be useful as reagentsfor studying metabolism of active vitamin D₃, that is,1α,25-dihydroxyvitamin D₃.

1. A compound having the formula:

where Z may be the same or different and represents a hydrogen atom or ahydroxy protecting group. 2.24,26,27-trihomo-1α,25-dihydroxy2β,2′-epoxy-22,24-dien-19-norvitamin D₃having the formula:


3. 24,26,27-trihomo-1α,25-dihydroxy2α,2′-epoxy-22,24-dien-19-norvitaminD₃ having the formula:


4. A method of preparing a compound of claim 1 comprising a step ofobtaining a compound represented by formula III

wherein Z may be the same or different and represents a hydrogen atom ora hydroxy protecting group and Ph represents a phenyl group, from acompound represented by formula II

wherein Z may be the same or different and represents a hydrogen atom ora hydroxy protecting group.